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1
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Ahern DT, Bansal P, Faustino IV, Chambers OM, Banda EC, Glatt-Deeley HR, Massey RE, Kondaveeti Y, Pinter SF. Isogenic hiPSC models of Turner syndrome development reveal shared roles of inactive X and Y in the human cranial neural crest network. Am J Hum Genet 2025; 112:615-629. [PMID: 39922196 PMCID: PMC11947172 DOI: 10.1016/j.ajhg.2025.01.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 01/13/2025] [Accepted: 01/16/2025] [Indexed: 02/10/2025] Open
Abstract
Viable human aneuploidy can be challenging to model in rodents due to syntenic boundaries or primate-specific biology. Human monosomy-X (45,X) causes Turner syndrome (TS), altering craniofacial, skeletal, endocrine, and cardiovascular development, which in contrast remain unaffected in X-monosomic mice. To learn how monosomy-X may impact embryonic development, we turned to 45,X and isogenic euploid human induced pluripotent stem cells (hiPSCs) from male and female mosaic donors. Because the neural crest (NC) is hypothesized to give rise to craniofacial and cardiovascular changes in TS, we assessed differential expression of hiPSC-derived anterior NC cells (NCCs). Across three independent isogenic panels, 45,X NCCs show impaired acquisition of PAX7+SOX10+ markers and disrupted expression of other NCC-specific genes relative to isogenic euploid controls. Additionally, 45,X NCCs increase cholesterol biosynthesis genes while reducing transcripts with 5' terminal oligopyrimidine (TOP) motifs, including those of ribosomal and nuclear-encoded mitochondrial proteins. Such metabolic pathways are also over-represented in weighted co-expression modules that are preserved in monogenic neurocristopathy and reflect 28% of all TS-associated terms of the human phenotype ontology. We demonstrate that 45,X NCCs reduce protein synthesis despite activation of mammalian target of rapamycin (mTOR) but are partially rescued by mild mTOR suppression. Our analysis identifies specific sex-linked genes that are expressed from two copies in euploid males and females alike and qualify as candidate haploinsufficient drivers of TS phenotypes in NC-derived lineages. This study demonstrates that isogenic hiPSC-derived NCC panels representing monosomy-X can serve as powerful models of early NC development in TS and inform new hypotheses toward its etiology.
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Affiliation(s)
- Darcy T Ahern
- Graduate Program in Genetics and Developmental Biology, UCONN Health, University of Connecticut, Farmington, CT, USA; Department of Genetics and Genome Sciences, UCONN Health, University of Connecticut, Farmington, CT, USA
| | - Prakhar Bansal
- Graduate Program in Genetics and Developmental Biology, UCONN Health, University of Connecticut, Farmington, CT, USA; Department of Genetics and Genome Sciences, UCONN Health, University of Connecticut, Farmington, CT, USA
| | - Isaac V Faustino
- Department of Genetics and Genome Sciences, UCONN Health, University of Connecticut, Farmington, CT, USA
| | - Owen M Chambers
- Department of Genetics and Genome Sciences, UCONN Health, University of Connecticut, Farmington, CT, USA
| | - Erin C Banda
- Department of Genetics and Genome Sciences, UCONN Health, University of Connecticut, Farmington, CT, USA
| | - Heather R Glatt-Deeley
- Department of Genetics and Genome Sciences, UCONN Health, University of Connecticut, Farmington, CT, USA
| | - Rachael E Massey
- Graduate Program in Genetics and Developmental Biology, UCONN Health, University of Connecticut, Farmington, CT, USA; Department of Genetics and Genome Sciences, UCONN Health, University of Connecticut, Farmington, CT, USA; Institute for Systems Genomics, University of Connecticut, Farmington, CT, USA
| | - Yuvabharath Kondaveeti
- Department of Genetics and Genome Sciences, UCONN Health, University of Connecticut, Farmington, CT, USA
| | - Stefan F Pinter
- Graduate Program in Genetics and Developmental Biology, UCONN Health, University of Connecticut, Farmington, CT, USA; Department of Genetics and Genome Sciences, UCONN Health, University of Connecticut, Farmington, CT, USA; Institute for Systems Genomics, University of Connecticut, Farmington, CT, USA.
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2
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Ansere VA, Kim SS, Marino F, Morillo K, Dubal DB, Murphy CT, Suh Y, Benayoun BA. Strategies for studying sex differences in brain aging. Trends Genet 2025:S0168-9525(25)00027-7. [PMID: 40037936 DOI: 10.1016/j.tig.2025.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Revised: 02/06/2025] [Accepted: 02/07/2025] [Indexed: 03/06/2025]
Abstract
Studying sex effects and their underlying mechanisms is of major relevance to understanding brain health. Despite growing interests, experimentally studying sex differences, particularly in the context of aging, remains challenging. Since sex chromosomal content influences gonadal development, separating the effects of gonadal hormones and chromosomal factors requires specific model systems. Here, we highlight rodent and tractable models for examining sex dimorphism in brain and cognitive aging. In addition, we discuss multi-omic and bioinformatic approaches that yield biological insights from animal and human studies. This review provides a comprehensive overview of the diverse toolkit now available to advance our understanding of sex differences in brain aging.
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Affiliation(s)
- Victor A Ansere
- Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA
| | - Seung-Soo Kim
- Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Francesca Marino
- Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, CA, USA
| | - Katherine Morillo
- Department of Molecular Biology, Princeton University, Princeton, NJ, USA
| | - Dena B Dubal
- Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, CA, USA.
| | - Coleen T Murphy
- Department of Molecular Biology, Princeton University, Princeton, NJ, USA; LSI Genomics, Princeton University, Princeton, NJ, USA.
| | - Yousin Suh
- Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA.
| | - Bérénice A Benayoun
- Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA; Molecular and Computational Biology Department, USC Dornsife College of Letters, Arts and Sciences, Los Angeles, CA 90089, USA; Biochemistry and Molecular Medicine Department, USC Keck School of Medicine, Los Angeles, CA 90089, USA.
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3
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Abdulai-Saiku S, Gupta S, Wang D, Marino F, Moreno AJ, Huang Y, Srivastava D, Panning B, Dubal DB. The maternal X chromosome affects cognition and brain ageing in female mice. Nature 2025; 638:152-159. [PMID: 39843739 PMCID: PMC11798838 DOI: 10.1038/s41586-024-08457-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 11/27/2024] [Indexed: 01/24/2025]
Abstract
Female mammalian cells have two X chromosomes, one of maternal origin and one of paternal origin. During development, one X chromosome randomly becomes inactivated1-4. This renders either the maternal X (Xm) chromosome or the paternal X (Xp) chromosome inactive, causing X mosaicism that varies between female individuals, with some showing considerable or complete skew of the X chromosome that remains active5-7. Parent-of-X origin can modify epigenetics through DNA methylation8,9 and possibly gene expression; thus, mosaicism could buffer dysregulated processes in ageing and disease. However, whether X skew or its mosaicism alters functions in female individuals is largely unknown. Here we tested whether skew towards an active Xm chromosome influences the brain and body-and then delineated unique features of Xm neurons and Xp neurons. An active Xm chromosome impaired cognition in female mice throughout the lifespan and led to worsened cognition with age. Cognitive deficits were accompanied by Xm-mediated acceleration of biological or epigenetic ageing of the hippocampus, a key centre for learning and memory, in female mice. Several genes were imprinted on the Xm chromosome of hippocampal neurons, suggesting silenced cognitive loci. CRISPR-mediated activation of Xm-imprinted genes improved cognition in ageing female mice. Thus, the Xm chromosome impaired cognition, accelerated brain ageing and silenced genes that contribute to cognition in ageing. Understanding how Xm impairs brain function could lead to an improved understanding of heterogeneity in cognitive health in female individuals and to X-chromosome-derived pathways that protect against cognitive deficits and brain ageing.
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Affiliation(s)
- Samira Abdulai-Saiku
- Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA
| | - Shweta Gupta
- Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA
| | - Dan Wang
- Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA
| | - Francesca Marino
- Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA
- Neurosciences Graduate Program, University of California San Francisco, San Francisco, CA, USA
| | - Arturo J Moreno
- Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA
| | - Yu Huang
- Gladstone Institute of Cardiovascular Disease, San Francisco, CA, USA
| | - Deepak Srivastava
- Gladstone Institute of Cardiovascular Disease, San Francisco, CA, USA
- Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA
| | - Barbara Panning
- Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA
| | - Dena B Dubal
- Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.
- Neurosciences Graduate Program, University of California San Francisco, San Francisco, CA, USA.
- Bakar Aging Research Institute, University of California San Francisco, San Francisco, CA, USA.
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4
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Ahern DT, Bansal P, Faustino IV, Glatt-Deeley HR, Massey R, Kondaveeti Y, Banda EC, Pinter SF. Isogenic hiPSC models of Turner syndrome development reveal shared roles of inactive X and Y in the human cranial neural crest network. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.03.08.531747. [PMID: 36945647 PMCID: PMC10028916 DOI: 10.1101/2023.03.08.531747] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/13/2023]
Abstract
Modeling the developmental etiology of viable human aneuploidy can be challenging in rodents due to syntenic boundaries, or primate-specific biology. In humans, monosomy-X (45,X) causes Turner syndrome (TS), altering craniofacial, skeletal, endocrine, and cardiovascular development, which in contrast remain unaffected in 39,X-mice. To learn how human monosomy-X may impact early embryonic development, we turned to human 45,X and isogenic euploid induced pluripotent stem cells (hiPSCs) from male and female mosaic donors. Because neural crest (NC) derived cell types are hypothesized to underpin craniofacial and cardiovascular changes in TS, we performed a highly-powered differential expression study on hiPSC-derived anterior neural crest cells (NCCs). Across three independent isogenic panels, 45,X NCCs show impaired acquisition of PAX7+SOX10+ markers, and disrupted expression of other NCC-specific genes, relative to their isogenic euploid controls. In particular, 45,X NCCs increase cholesterol biosynthesis genes while reducing transcripts that feature 5' terminal oligopyrimidine (TOP) motifs, including those of ribosomal protein and nuclear-encoded mitochondrial genes. Such metabolic pathways are also over-represented in weighted co-expression gene modules that are preserved in monogenic neurocristopathy. Importantly, these gene modules are also significantly enriched in 28% of all TS-associated terms of the human phenotype ontology. Our analysis identifies specific sex-linked genes that are expressed from two copies in euploid males and females alike and qualify as candidate haploinsufficient drivers of TS phenotypes in NC-derived lineages. This study demonstrates that isogenic hiPSC-derived NCC panels representing monosomy-X can serve as a powerful model of early NC development in TS and inform new hypotheses towards its etiology.
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Affiliation(s)
- Darcy T. Ahern
- Graduate Program in Genetics and Developmental Biology, UCONN Health, University of Connecticut, Farmington, CT, United States
- Department of Genetics and Genome Sciences, UCONN Health, University of Connecticut, Farmington, CT, United States
| | - Prakhar Bansal
- Graduate Program in Genetics and Developmental Biology, UCONN Health, University of Connecticut, Farmington, CT, United States
- Department of Genetics and Genome Sciences, UCONN Health, University of Connecticut, Farmington, CT, United States
| | - Isaac V. Faustino
- Department of Genetics and Genome Sciences, UCONN Health, University of Connecticut, Farmington, CT, United States
| | - Heather R. Glatt-Deeley
- Department of Genetics and Genome Sciences, UCONN Health, University of Connecticut, Farmington, CT, United States
| | - Rachael Massey
- Graduate Program in Genetics and Developmental Biology, UCONN Health, University of Connecticut, Farmington, CT, United States
- Department of Genetics and Genome Sciences, UCONN Health, University of Connecticut, Farmington, CT, United States
- Institute for Systems Genomics, University of Connecticut, Farmington, CT, United States
| | - Yuvabharath Kondaveeti
- Department of Genetics and Genome Sciences, UCONN Health, University of Connecticut, Farmington, CT, United States
| | - Erin C. Banda
- Department of Genetics and Genome Sciences, UCONN Health, University of Connecticut, Farmington, CT, United States
| | - Stefan F. Pinter
- Graduate Program in Genetics and Developmental Biology, UCONN Health, University of Connecticut, Farmington, CT, United States
- Department of Genetics and Genome Sciences, UCONN Health, University of Connecticut, Farmington, CT, United States
- Institute for Systems Genomics, University of Connecticut, Farmington, CT, United States
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5
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Kundakovic M, Tickerhoof M. Epigenetic mechanisms underlying sex differences in the brain and behavior. Trends Neurosci 2024; 47:18-35. [PMID: 37968206 PMCID: PMC10841872 DOI: 10.1016/j.tins.2023.09.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 08/21/2023] [Accepted: 09/26/2023] [Indexed: 11/17/2023]
Abstract
Sex differences are found across brain regions, behaviors, and brain diseases. Sexual differentiation of the brain is initiated prenatally but it continues throughout life, as a result of the interaction of three major factors: gonadal hormones, sex chromosomes, and the environment. These factors are thought to act, in part, via epigenetic mechanisms which control chromatin and transcriptional states in brain cells. In this review, we discuss evidence that epigenetic mechanisms underlie sex-specific neurobehavioral changes during critical organizational periods, across the estrous cycle, and in response to diverse environments throughout life. We further identify future directions for the field that will provide novel mechanistic insights into brain sex differences, inform brain disease treatments and women's brain health in particular, and apply to people across genders.
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Affiliation(s)
- Marija Kundakovic
- Department of Biological Sciences, Fordham University, Bronx, NY 10458, USA.
| | - Maria Tickerhoof
- Department of Biological Sciences, Fordham University, Bronx, NY 10458, USA
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6
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Rocks D, Jaric I, Bellia F, Cham H, Greally JM, Suzuki M, Kundakovic M. Early-life stress and ovarian hormones alter transcriptional regulation in the nucleus accumbens resulting in sex-specific responses to cocaine. Cell Rep 2023; 42:113187. [PMID: 37777968 PMCID: PMC10753961 DOI: 10.1016/j.celrep.2023.113187] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 07/29/2023] [Accepted: 09/12/2023] [Indexed: 10/03/2023] Open
Abstract
Early-life stress and ovarian hormones contribute to increased female vulnerability to cocaine addiction. Here, we reveal molecular substrates in the reward area, the nucleus accumbens, through which these female-specific factors affect immediate and conditioning responses to cocaine. We find shared involvement of X chromosome inactivation-related and estrogen signaling-related gene regulation in enhanced conditioning responses following early-life stress and during the low-estrogenic state in females. Low-estrogenic females respond to acute cocaine by opening neuronal chromatin enriched for the sites of ΔFosB, a transcription factor implicated in chronic cocaine response and addiction. Conversely, high-estrogenic females respond to cocaine by preferential chromatin closing, providing a mechanism for limiting cocaine-driven chromatin and synaptic plasticity. We find that physiological estrogen withdrawal, early-life stress, and absence of one X chromosome all nullify the protective effect of a high-estrogenic state on cocaine conditioning in females. Our findings offer a molecular framework to enable understanding of sex-specific neuronal mechanisms underlying cocaine use disorder.
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Affiliation(s)
- Devin Rocks
- Department of Biological Sciences, Fordham University, Bronx, NY, USA
| | - Ivana Jaric
- Department of Biological Sciences, Fordham University, Bronx, NY, USA
| | - Fabio Bellia
- Department of Biological Sciences, Fordham University, Bronx, NY, USA
| | - Heining Cham
- Department of Psychology, Fordham University, Bronx, NY, USA
| | - John M Greally
- Center for Epigenomics, Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Masako Suzuki
- Center for Epigenomics, Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA; Department of Nutrition, Texas A&M University, College Station, TX, USA
| | - Marija Kundakovic
- Department of Biological Sciences, Fordham University, Bronx, NY, USA.
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7
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Monosomy X in isogenic human iPSC-derived trophoblast model impacts expression modules preserved in human placenta. Proc Natl Acad Sci U S A 2022; 119:e2211073119. [PMID: 36161909 DOI: 10.1073/pnas.2211073119] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Mammalian sex chromosomes encode homologous X/Y gene pairs that were retained on the Y chromosome in males and escape X chromosome inactivation (XCI) in females. Inferred to reflect X/Y pair dosage sensitivity, monosomy X is a leading cause of miscarriage in humans with near full penetrance. This phenotype is shared with many other mammals but not the mouse, which offers sophisticated genetic tools to generate sex chromosomal aneuploidy but also tolerates its developmental impact. To address this critical gap, we generated X-monosomic human induced pluripotent stem cells (hiPSCs) alongside otherwise isogenic euploid controls from male and female mosaic samples. Phased genomic variants in these hiPSC panels enable systematic investigation of X/Y dosage-sensitive features using in vitro models of human development. Here, we demonstrate the utility of these validated hiPSC lines to test how X/Y-linked gene dosage impacts a widely used model for human syncytiotrophoblast development. While these isogenic panels trigger a GATA2/3- and TFAP2A/C-driven trophoblast gene circuit irrespective of karyotype, differential expression implicates monosomy X in altered levels of placental genes and in secretion of placental growth factor (PlGF) and human chorionic gonadotropin (hCG). Remarkably, weighted gene coexpression network modules that significantly reflect these changes are also preserved in first-trimester chorionic villi and term placenta. Our results suggest monosomy X may skew trophoblast cell type composition and function, and that the combined haploinsufficiency of the pseudoautosomal region likely plays a key role in these changes.
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8
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Álvarez-Nava F, Soto-Quintana M. The Hypothesis of the Prolonged Cell Cycle in Turner Syndrome. J Dev Biol 2022; 10:16. [PMID: 35645292 PMCID: PMC9149809 DOI: 10.3390/jdb10020016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 03/13/2022] [Indexed: 01/27/2023] Open
Abstract
Turner syndrome (TS) is a chromosomal disorder that is caused by a missing or structurally abnormal second sex chromosome. Subjects with TS are at an increased risk of developing intrauterine growth retardation, low birth weight, short stature, congenital heart diseases, infertility, obesity, dyslipidemia, hypertension, insulin resistance, type 2 diabetes mellitus, metabolic syndrome, and cardiovascular diseases (stroke and myocardial infarction). The underlying pathogenetic mechanism of TS is unknown. The assumption that X chromosome-linked gene haploinsufficiency is associated with the TS phenotype is questioned since such genes have not been identified. Thus, other pathogenic mechanisms have been suggested to explain this phenotype. Morphogenesis encompasses a series of events that includes cell division, the production of migratory precursors and their progeny, differentiation, programmed cell death, and integration into organs and systems. The precise control of the growth and differentiation of cells is essential for normal development. The cell cycle frequency and the number of proliferating cells are essential in cell growth. 45,X cells have a failure to proliferate at a normal rate, leading to a decreased cell number in a given tissue during organogenesis. A convergence of data indicates an association between a prolonged cell cycle and the phenotypical features in Turner syndrome. This review aims to examine old and new findings concerning the relationship between a prolonged cell cycle and TS phenotype. These studies reveal a diversity of phenotypic features in TS that could be explained by reduced cell proliferation. The implications of this hypothesis for our understanding of the TS phenotype and its pathogenesis are discussed. It is not surprising that 45,X monosomy leads to cellular growth pathway dysregulation with profound deleterious effects on both embryonic and later stages of development. The prolonged cell cycle could represent the beginning of the pathogenesis of TS, leading to a series of phenotypic consequences in embryonic/fetal, neonatal, pediatric, adolescence, and adulthood life.
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Affiliation(s)
- Francisco Álvarez-Nava
- Biological Sciences School, Faculty of Biological Sciences, Central University of Ecuador, Quito 170113, Ecuador
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9
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Davies W. The contribution of Xp22.31 gene dosage to Turner and Klinefelter syndromes and sex-biased phenotypes. Eur J Med Genet 2021; 64:104169. [PMID: 33610733 DOI: 10.1016/j.ejmg.2021.104169] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 01/11/2021] [Accepted: 02/16/2021] [Indexed: 11/27/2022]
Abstract
Turner syndrome (TS) is a rare developmental condition in females caused by complete, or partial, loss of the second sex chromosome; it is associated with a number of phenotypes including short stature, ovarian failure and infertility, as well as neurobehavioural and cognitive manifestations. In contrast, Klinefelter syndrome (KS) arises from an excess of X chromosome material in males (typical karyotype is 47,XXY); like TS, KS is associated with infertility and hormonal imbalance, and behavioural/neurocognitive differences from gonadal sex-matched counterparts. Lower dosage of genes that escape X-inactivation may partially explain TS phenotypes, whilst overdosage of these genes may contribute towards KS-related symptoms. Here, I discuss new findings from individuals with deletions or duplications limited to Xp22.31 (a region escaping X-inactivation), and consider the extent to which altered gene dosage within this small interval (and of the steroid sulfatase (STS) gene in particular) may influence the phenotypic profiles of TS and KS. The expression of X-escapees can be higher in female than male tissues; I conclude by considering how lower Xp22.31 gene dosage in males may increase their likelihood of exhibiting particular phenotypes relative to females. Understanding the genetic contribution to specific phenotypes in rare disorders such as TS and KS, and to more common sex-biased phenotypes, will be important for developing more effective, and more personalised, therapeutic approaches.
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Affiliation(s)
- William Davies
- School of Psychology, Cardiff University, Cardiff, UK; Division of Psychological Medicine and Clinical Neurosciences and Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK; Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK.
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10
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Sigurdardottir HL, Lanzenberger R, Kranz GS. Genetics of sex differences in neuroanatomy and function. HANDBOOK OF CLINICAL NEUROLOGY 2020; 175:179-193. [PMID: 33008524 DOI: 10.1016/b978-0-444-64123-6.00013-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/25/2023]
Abstract
Sex differences are observed at many distinct biologic levels, such as in the anatomy and functioning of the brain, behavior, and susceptibility to neuropsychiatric disorders. Previously, these differences were believed to entirely result from the secretion of gonadal hormones; however, recent research has demonstrated that differences are also the consequence of direct or nonhormonal effects of genes located on the sex chromosomes. This chapter reviews the four core genotype model that separates the effects of hormones and sex chromosomes and highlights a few genes that are believed to be partly responsible for sex dimorphism of the brain, in particular, the Sry gene. Genetics of the brain's neurochemistry is discussed and the susceptibility to certain neurologic and psychiatric disorders is reviewed. Lastly, we discuss the sex-specific genetic contribution in disorders of sexual development. The precise molecular mechanisms underlying these differences are currently not entirely known. An increased knowledge and understanding of the role of candidate genes will undeniably be of great aid in elucidating the molecular basis of sex-biased disorders and potentially allow for more sex-specific therapies.
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Affiliation(s)
- Helen L Sigurdardottir
- Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria.
| | - Rupert Lanzenberger
- Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria
| | - Georg S Kranz
- Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria; Department of Rehabilitation Sciences, The Hong Kong Polytechnic University, Hong Kong, People's Republic of China; The State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong, People's Republic of China
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11
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Pinares-Garcia P, Stratikopoulos M, Zagato A, Loke H, Lee J. Sex: A Significant Risk Factor for Neurodevelopmental and Neurodegenerative Disorders. Brain Sci 2018; 8:E154. [PMID: 30104506 PMCID: PMC6120011 DOI: 10.3390/brainsci8080154] [Citation(s) in RCA: 122] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 08/08/2018] [Accepted: 08/10/2018] [Indexed: 12/11/2022] Open
Abstract
Males and females sometimes significantly differ in their propensity to develop neurological disorders. Females suffer more from mood disorders such as depression and anxiety, whereas males are more susceptible to deficits in the dopamine system including Parkinson's disease (PD), attention-deficit hyperactivity disorder (ADHD) and autism. Despite this, biological sex is rarely considered when making treatment decisions in neurological disorders. A better understanding of the molecular mechanism(s) underlying sex differences in the healthy and diseased brain will help to devise diagnostic and therapeutic strategies optimal for each sex. Thus, the aim of this review is to discuss the available evidence on sex differences in neuropsychiatric and neurodegenerative disorders regarding prevalence, progression, symptoms and response to therapy. We also discuss the sex-related factors such as gonadal sex hormones and sex chromosome genes and how these might help to explain some of the clinically observed sex differences in these disorders. In particular, we highlight the emerging role of the Y-chromosome gene, SRY, in the male brain and its potential role as a male-specific risk factor for disorders such as PD, autism, and ADHD in many individuals.
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Affiliation(s)
- Paulo Pinares-Garcia
- Brain and Gender laboratory, Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.
- Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria 3168, Australia.
| | - Marielle Stratikopoulos
- Brain and Gender laboratory, Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.
- Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria 3168, Australia.
| | - Alice Zagato
- Brain and Gender laboratory, Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.
- School of Life and Environmental Sciences, Deakin University, Burwood, Victoria 3125, Australia.
| | - Hannah Loke
- Brain and Gender laboratory, Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.
| | - Joohyung Lee
- Brain and Gender laboratory, Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.
- Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria 3168, Australia.
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12
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Sex chromosomes drive gene expression and regulatory dimorphisms in mouse embryonic stem cells. Biol Sex Differ 2017; 8:28. [PMID: 28818098 PMCID: PMC5561606 DOI: 10.1186/s13293-017-0150-x] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Accepted: 08/10/2017] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Pre-implantation embryos exhibit sexual dimorphisms in both primates and rodents. To determine whether these differences reflected sex-biased expression patterns, we generated transcriptome profiles for six 40,XX, six 40,XY, and two 39,X mouse embryonic stem (ES) cells by RNA sequencing. RESULTS We found hundreds of coding and non-coding RNAs that were differentially expressed between male and female cells. Surprisingly, the majority of these were autosomal and included RNA encoding transcription and epigenetic and chromatin remodeling factors. We showed differential Prdm14-responsive enhancer activity in male and female cells, correlating with the sex-specific levels of Prdm14 expression. This is the first time sex-specific enhancer activity in ES cells has been reported. Evaluation of X-linked gene expression patterns between our XX and XY lines revealed four distinct categories: (1) genes showing 2-fold greater expression in the female cells; (2) a set of genes with expression levels well above 2-fold in female cells; (3) genes with equivalent RNA levels in male and female cells; and strikingly, (4) a small number of genes with higher expression in the XY lines. Further evaluation of autosomal gene expression revealed differential expression of imprinted loci, despite appropriate parent-of-origin patterns. The 39,X lines aligned closely with the XY cells and provided insights into potential regulation of genes associated with Turner syndrome in humans. Moreover, inclusion of the 39,X lines permitted three-way comparisons, delineating X and Y chromosome-dependent patterns. CONCLUSIONS Overall, our results support the role of the sex chromosomes in establishing sex-specific networks early in embryonic development and provide insights into effects of sex chromosome aneuploidies originating at those stages.
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Green T, Naylor PE, Davies W. Attention deficit hyperactivity disorder (ADHD) in phenotypically similar neurogenetic conditions: Turner syndrome and the RASopathies. J Neurodev Disord 2017; 9:25. [PMID: 28694877 PMCID: PMC5502326 DOI: 10.1186/s11689-017-9205-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Accepted: 05/18/2017] [Indexed: 11/17/2022] Open
Abstract
Background ADHD (attention deficit hyperactivity disorder) is a common neurodevelopmental disorder. There has been extensive clinical and basic research in the field of ADHD over the past 20 years, but the mechanisms underlying ADHD risk are multifactorial, complex and heterogeneous and, as yet, are poorly defined. In this review, we argue that one approach to address this challenge is to study well-defined disorders to provide insights into potential biological pathways that may be involved in idiopathic ADHD. Main body To address this premise, we selected two neurogenetic conditions that are associated with significantly increased ADHD risk: Turner syndrome and the RASopathies (of which Noonan syndrome and neurofibromatosis type 1 are the best-defined with regard to ADHD-related phenotypes). These syndromes were chosen for two main reasons: first, because intellectual functioning is relatively preserved, and second, because they are strikingly phenotypically similar but are etiologically distinct. We review the cognitive, behavioural, neural and cellular phenotypes associated with these conditions and examine their relevance as a model for idiopathic ADHD. Conclusion We conclude by discussing current and future opportunities in the clinical and basic research of these conditions, which, in turn, may shed light upon the biological pathways underlying idiopathic ADHD.
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Affiliation(s)
- Tamar Green
- Center for Interdisciplinary Brain Sciences Research, Stanford University School of Medicine, Stanford, USA
| | - Paige E Naylor
- Department of Clinical Psychology, Palo Alto University, Palo Alto, CA USA
| | - William Davies
- Medical Research Council Centre for Neuropsychiatric Genetics and Genomics and Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.,School of Psychology, Cardiff University, Tower Building, 70, Park Place, Cardiff, CF10 3AT UK.,Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK
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14
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Zhao C, Gong G. Mapping the effect of the X chromosome on the human brain: Neuroimaging evidence from Turner syndrome. Neurosci Biobehav Rev 2017; 80:263-275. [PMID: 28591595 DOI: 10.1016/j.neubiorev.2017.05.023] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Revised: 04/07/2017] [Accepted: 05/26/2017] [Indexed: 10/19/2022]
Abstract
In addition to determining sex, the X chromosome has long been considered to play a crucial role in brain development and intelligence. Turner syndrome (TS) is caused by the congenital absence of all or part of one of the X chromosomes in females. Thus, Turner syndrome provides a unique "knock-out model" for investigating how the X chromosome influences the human brain in vivo. Numerous cutting-edge neuroimaging techniques and analyses have been applied to investigate various brain phenotypes in women with TS, which have yielded valuable evidence toward elucidating the causal relationship between the X chromosome and human brain structure and function. In this review, we comprehensively summarize the recent progress made in TS-related neuroimaging studies and emphasize how these findings have enhanced our understanding of X chromosome function with respect to the human brain. Future investigations are encouraged to address the issues of previous TS neuroimaging studies and to further identify the biological mechanisms that underlie the function of specific X-linked genes in the human brain.
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Affiliation(s)
- Chenxi Zhao
- State Key Laboratory of Cognitive Neuroscience and Learning & IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing 100875, China
| | - Gaolang Gong
- State Key Laboratory of Cognitive Neuroscience and Learning & IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing 100875, China; Beijing Key Laboratory of Brain Imaging and Connectomics, Beijing Normal University, Beijing 100875, China.
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15
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Abstract
Reproduction across mammalian species is conserved with a general pattern of fertilization followed by nascent embryo development in transcriptional silence for a variable length of time, a series of cleavage divisions that occur without growth in size of the embryo, compaction to form a morula, and production of a blastocyst. Following blastocyst formation, the embryo may implant immediately or after substantial differentiation of the epiblast and hypoblast layers. In this chapter, the shared and unique properties of several species, commonly used in studies of reproduction and embryology, are outlined.
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Affiliation(s)
| | - L Prezzoto
- Agricultural Research Centers, Montana State University, Bozeman, MT, United States
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16
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Preliminary Evidence for Aortopathy and an X-Linked Parent-of-Origin Effect on Aortic Valve Malformation in a Mouse Model of Turner Syndrome. J Cardiovasc Dev Dis 2015; 2:190-199. [PMID: 29371518 PMCID: PMC5753145 DOI: 10.3390/jcdd2030190] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2015] [Revised: 07/07/2015] [Accepted: 07/07/2015] [Indexed: 01/15/2023] Open
Abstract
Turner syndrome (TS), most frequently caused by X-monosomy (45,X), is characterized in part by cardiovascular abnormalities, including aortopathy and bicuspid aortic valve (BAV). There is a need for animal models that recapitulate the cardiovascular manifestations of TS. Extracellular matrix (ECM) organization and morphometrics of the aortic valve and proximal aorta were examined in adult 39,XO mice (where the parental origin of the single X was paternal (39,XPO) or maternal (39,XMO)) and 40,XX controls. Aortic valve morphology was normal (tricuspid) in all of the 39,XPO and 40,XX mice studied, but abnormal (bicuspid or quadricuspid) in 15% of 39,XMO mice. Smooth muscle cell orientation in the ascending aorta was abnormal in all 39,XPO and 39,XMO mice examined, but smooth muscle actin was decreased in 39,XMO mice only. Aortic dilation was present with reduced penetrance in 39,XO mice. The 39,XO mouse demonstrates aortopathy and an X-linked parent-of-origin effect on aortic valve malformation, and the candidate gene FAM9B is polymorphically expressed in control and diseased human aortic valves. The 39,XO mouse model may be valuable for examining the mechanisms underlying the cardiovascular findings in TS, and suggest there are important genetic modifiers on the X chromosome that modulate risk for nonsyndromic BAV and aortopathy.
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17
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Loke H, Harley V, Lee J. Biological factors underlying sex differences in neurological disorders. Int J Biochem Cell Biol 2015; 65:139-50. [PMID: 26028290 DOI: 10.1016/j.biocel.2015.05.024] [Citation(s) in RCA: 106] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2015] [Revised: 05/25/2015] [Accepted: 05/26/2015] [Indexed: 11/28/2022]
Abstract
The prevalence, age of onset, pathophysiology, and symptomatology of many neurological and neuropsychiatric conditions differ significantly between males and females. Females suffer more from mood disorders such as depression and anxiety, whereas males are more susceptible to deficits in the dopamine system including Parkinson's disease (PD), attention-deficit hyperactivity disorder (ADHD), schizophrenia, and autism spectrum disorders (ASD). Until recently, these sex differences have been explained solely by the neuroprotective actions of sex hormones in females. Emerging evidence however indicates that the sex chromosome genes (i.e. X- and Y-linked genes) also contribute to brain sex differences. In particular, the Y-chromosome gene, SRY (Sex-determining Region on the Y chromosome) is an interesting candidate as it is expressed in dopamine-abundant brain regions, where it regulates dopamine biosynthesis and dopamine-mediated functions such as voluntary movement in males. Furthermore, SRY expression is dysregulated in a toxin-induced model of PD, suggesting a role for SRY in the pathogenesis of dopamine cells. Taken together, these studies highlight the importance of understanding the interplay between sex-specific hormones and sex-specific genes in healthy and diseased brain. In particular, better understanding of regulation and function of SRY in the male brain could provide entirely novel and important insights into genetic factors involved in the susceptibility of men to neurological disorders, as well as development of novel sex-specific therapies.
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Affiliation(s)
- Hannah Loke
- Hudson Institute of Medical Research, Clayton, VIC, Australia; Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia
| | - Vincent Harley
- Hudson Institute of Medical Research, Clayton, VIC, Australia; Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia; Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia.
| | - Joohyung Lee
- Hudson Institute of Medical Research, Clayton, VIC, Australia; Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia; Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia.
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18
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Raznahan A, Lue Y, Probst F, Greenstein D, Giedd J, Wang C, Lerch J, Swerdloff R. Triangulating the sexually dimorphic brain through high-resolution neuroimaging of murine sex chromosome aneuploidies. Brain Struct Funct 2014; 220:3581-93. [PMID: 25146308 DOI: 10.1007/s00429-014-0875-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2014] [Accepted: 08/09/2014] [Indexed: 12/11/2022]
Abstract
Murine sex chromosome aneuploidies (SCAs) provide powerful models for charting sex chromosome influences on mammalian brain development. Here, building on prior work in X-monosomic (XO) mice, we use spatially non-biased high-resolution imaging to compare and contrast neuroanatomical alterations in XXY and XO mice relative to their wild-type XX and XY littermates. First, we show that carriage of a supernumerary X chromosome in XXY males (1) does not prevent normative volumetric masculinization of the bed nucleus of the stria terminalis (BNST) and medial amygdala, but (2) causes distributed anatomical alterations relative to XY males, which show a statistically unexpected tendency to be co-localized with and reciprocal to XO-XX differences in anatomy. These overlaps identify the lateral septum, BNST, ventral group thalamic nuclei and periaqueductal gray matter as regions with replicable sensitivity to X chromosome dose across two SCAs. We then harness anatomical variation across all four karyotype groups in our study--XO, XX, XY and XXY--to create an agnostic data-driven segmentation of the mouse brain into five distributed clusters which (1) recover fundamental properties of brain organization with high spatial precision, (2) define two previously uncharacterized systems of relative volume excess in females vs. males ("forebrain cholinergic" and "cerebelo-pontine-thalamo-cortical"), and (3) adopt stereotyped spatial motifs which delineate ordered gradients of sex chromosome and gonadal influences on volumetric brain development. Taken together, these data provide a new framework for the study of sexually dimorphic influences on brain development in health and disrupted brain development in SCA.
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Affiliation(s)
- Armin Raznahan
- Child Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Rm 4C108, Building 20, 10 Center Drive, Bethesda, MD, 20815, USA.
| | - YanHe Lue
- Division of Endocrinology, Department of Medicine, Los Angele Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Frank Probst
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Deanna Greenstein
- Child Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Rm 4C108, Building 20, 10 Center Drive, Bethesda, MD, 20815, USA
| | - Jay Giedd
- Child Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Rm 4C108, Building 20, 10 Center Drive, Bethesda, MD, 20815, USA
| | - Christina Wang
- Division of Endocrinology, Department of Medicine, Los Angele Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Jason Lerch
- Mouse Imaging Centre and Program in Neuroscience and Mental, The Hospital for Sick Children Hospital, Toronto, ON, Canada
| | - Ronald Swerdloff
- Division of Endocrinology, Department of Medicine, Los Angele Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
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19
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Davies W. Sex differences in attention Deficit Hyperactivity Disorder: candidate genetic and endocrine mechanisms. Front Neuroendocrinol 2014; 35:331-46. [PMID: 24680800 DOI: 10.1016/j.yfrne.2014.03.003] [Citation(s) in RCA: 91] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2013] [Revised: 02/13/2014] [Accepted: 03/17/2014] [Indexed: 02/07/2023]
Abstract
Attention Deficit Hyperactivity Disorder (ADHD) is a developmental condition characterised by severe inattention, pathological impulsivity and hyperactivity; it is relatively common affecting up to 6% of children, and is associated with a risk of long-term adverse educational and social consequences. Males are considerably more likely to be diagnosed with ADHD than females; the course of the disorder and its associated co-morbidities also appear to be sensitive to sex. Here, I discuss fundamental biological (genetic and endocrine) mechanisms that have been shown to, or could theoretically, contribute towards these sexually dimorphic phenomena. Greater understanding of how and why the sexes differ with respect to ADHD vulnerability should allow us to identify and characterise novel protective and risk factors for the disorder, and should ultimately facilitate improved diagnosis, prognosis and treatment.
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Affiliation(s)
- William Davies
- Behavioural Genetics Group, Neuroscience and Mental Health Research Institute, Schools of Psychology and Medicine, Cardiff University, Tower Building, Park Place, Cardiff CF10 3AT, UK; Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Hadyn Ellis Building, Cardiff CF24 4HQ, UK.
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20
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Mueller SC, Grissom EM, Dohanich GP. Assessing gonadal hormone contributions to affective psychopathologies across humans and animal models. Psychoneuroendocrinology 2014; 46:114-28. [PMID: 24882164 DOI: 10.1016/j.psyneuen.2014.04.015] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2014] [Revised: 04/15/2014] [Accepted: 04/21/2014] [Indexed: 10/25/2022]
Abstract
Despite increasing acknowledgement of hormonal contributions to mood and anxiety disorders, the underlying mechanisms by which gonadal hormones influence psychopathology-related behaviours remain unknown. This review focuses on recent research that examines the influence of gonadal steroid hormones, including androgens, oestrogens, and progesterone, on mood and anxiety-related behaviours in human health and disease. To this aim, the literature was surveyed for studies that assess conditions with suspected underlying hormonal imbalances in otherwise healthy participants (e.g., premenstrual dysphoric disorder, postmenopausal depression) as well as conditions linked to congenital endocrine abnormalities (e.g., Turner Syndrome, Klinefelter Syndrome, polycystic ovary syndrome, congenital adrenal hyperplasia, familial male precocious puberty, androgen insensitivity syndrome). Furthermore, to better inform clinical work and to create a translational bridge, a second goal was to set human psychopathologies and animal models of these conditions side-by-side. In the second part of the review, based on consistencies revealed in the existing literature across conditions, a new model for the impact of gonadal hormones on anxious and depressed behavioural states is proposed. Finally, we conclude by proposing directions for future research, including the development of specific tasks suitable for cross-species comparisons to increase our knowledge of the role of gonadal hormones in mood and anxiety.
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Affiliation(s)
- S C Mueller
- Department of Experimental Clinical and Health Psychology, Ghent University, Ghent, Belgium.
| | - E M Grissom
- Department of Psychology, Tulane University, New Orleans, LA, USA
| | - G P Dohanich
- Department of Psychology, Tulane University, New Orleans, LA, USA; Program in Neuroscience, Tulane University, New Orleans, LA, USA
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21
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Abramowitz LK, Olivier-Van Stichelen S, Hanover JA. Chromosome imbalance as a driver of sex disparity in disease. J Genomics 2014; 2:77-88. [PMID: 25031659 PMCID: PMC4091450 DOI: 10.7150/jgen.8123] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
It has long been recognized that men and women exhibit different risks for diverse disorders ranging from metabolic to autoimmune diseases. However, the underlying causes of these disparities remain obscure. Analysis of patients with chromosomal abnormalities, including Turner syndrome (45X) and Klinefelter syndrome (47XXY), has highlighted the importance of X-linked gene dosage as a contributing factor for disease susceptibility. Escape from X-inactivation and X-linked imprinting can result in transcriptional differences between normal men and women as well as in patients with sex chromosome abnormalities. Animal models support a role for X-linked gene dosage in disease with O-linked N-acetylglucosamine transferase (OGT) emerging as a prime candidate for a pleiotropic effector. OGT encodes a highly regulated nutrient-sensing epigenetic modifier with established links to immunity, metabolism and development.
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Affiliation(s)
- Lara K Abramowitz
- Laboratory of Cell and Molecular Biology, NIDDK, National Institutes of Health, Bethesda, MD 20892-0851, USA
| | | | - John A Hanover
- Laboratory of Cell and Molecular Biology, NIDDK, National Institutes of Health, Bethesda, MD 20892-0851, USA
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22
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Jung SY, Park JW, Kim DH, Jun YH, Lee JS, Lee JE. Mosaic Turner syndrome associated with schizophrenia. Ann Pediatr Endocrinol Metab 2014; 19:42-4. [PMID: 24926463 PMCID: PMC4049549 DOI: 10.6065/apem.2014.19.1.42] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2013] [Revised: 10/07/2013] [Accepted: 10/26/2013] [Indexed: 11/20/2022] Open
Abstract
Turner syndrome is a sex-chromosome disorder; occurring in 1 in 2,500 female births. There are sporadic few case reports of concomitant Turner syndrome with schizophrenia worldwide. Most Turner females had a 45,X monosomy, whereas the majority of comorbidity between Turner syndrome and schizophrenia had a mosaic karyotype (45,X/46,XX). We present a case of a 21-year-old woman with Turner syndrome, mosaic karyotype (45,X/46,XX), showing mental retardation, hypothyroidism, and schizophrenia. HOPA gene within Xq13 is related to mental retardation, hypothyroidism, and schizophrenia. Our case may be a potential clue which supports the hypothesis for involvement of genes on X chromosome in development of schizophrenia. Further studies including comorbid cases reports are need in order to discern the cause of schizophrenia in patients having Turner syndrome.
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Affiliation(s)
- Sook Young Jung
- Department of Pediatrics, Inha University Hospital, Inha University School of Medicine, Incheon, Korea
| | - Joo Won Park
- Inha University School of Medicine, Incheon, Korea
| | - Dong Hyun Kim
- Department of Pediatrics, Inha University Hospital, Inha University School of Medicine, Incheon, Korea
| | - Yong Hoon Jun
- Department of Pediatrics, Inha University Hospital, Inha University School of Medicine, Incheon, Korea
| | - Jeong Seop Lee
- Department of Psychiatry, Inha University Hospital, Inha University School of Medicine, Incheon, Korea
| | - Ji Eun Lee
- Department of Pediatrics, Inha University Hospital, Inha University School of Medicine, Incheon, Korea
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23
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Trent S, Davies W. Cognitive, behavioural and psychiatric phenotypes associated with steroid sulfatase deficiency. World J Transl Med 2013; 2:1-12. [DOI: 10.5528/wjtm.v2.i1.1] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2012] [Revised: 01/24/2013] [Accepted: 02/08/2013] [Indexed: 02/05/2023] Open
Abstract
The enzyme steroid sulfatase (STS) desulfates a variety of steroid compounds thereby altering their activity. STS is expressed in the skin, and its deficiency in this tissue has been linked to the dermatological condition X-linked ichthyosis. STS is also highly expressed in the developing and adult human brain, and in a variety of steroidogenic organs (including the placenta and gonads); therefore it has the potential to influence brain development and function directly and/or indirectly (through influencing the hormonal milieu). In this review, we first discuss evidence from human and animal model studies suggesting that STS deficiency might predispose to neurobehavioural abnormalities and certain psychiatric disorders. We subsequently discuss potential mechanisms that may underlie these vulnerabilities. The data described herein have potential implications for understanding the complete spectrum of clinical phenotypes associated with X-linked ichthyosis, and may indicate novel pathogenic mechanisms underlying psychological dysfunction in developmental disorders such as attention deficit hyperactivity disorder and Turner syndrome.
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24
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Using mouse models to investigate sex-linked genetic effects on brain, behaviour and vulnerability to neuropsychiatric disorders. Brain Res Bull 2013; 92:12-20. [DOI: 10.1016/j.brainresbull.2011.06.018] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2011] [Revised: 06/17/2011] [Accepted: 06/27/2011] [Indexed: 11/20/2022]
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25
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X-linked expressed single nucleotide polymorphisms and dosage compensation. Epigenomics 2012. [DOI: 10.1017/cbo9780511777271.041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
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26
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Sheppard O, Wiseman FK, Ruparelia A, Tybulewicz VLJ, Fisher EMC. Mouse models of aneuploidy. ScientificWorldJournal 2012; 2012:214078. [PMID: 22262951 PMCID: PMC3259538 DOI: 10.1100/2012/214078] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2011] [Accepted: 11/16/2011] [Indexed: 02/07/2023] Open
Abstract
Abnormalities of chromosome copy number are called aneuploidies and make up a large health load on the human population. Many aneuploidies are lethal because the resulting abnormal gene dosage is highly deleterious. Nevertheless, some whole chromosome aneuploidies can lead to live births. Alterations in the copy number of sections of chromosomes, which are also known as segmental aneuploidies, are also associated with deleterious effects. Here we examine how aneuploidy of whole chromosomes and segmental aneuploidy of chromosomal regions are modeled in the mouse. These models provide a whole animal system in which we aim to investigate the complex phenotype-genotype interactions that arise from alteration in the copy number of genes. Although our understanding of this subject is still in its infancy, already research in mouse models is highlighting possible therapies that might help alleviate the cognitive effects associated with changes in gene number. Thus, creating and studying mouse models of aneuploidy and copy number variation is important for understanding what it is to be human, in both the normal and genomically altered states.
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Affiliation(s)
- Olivia Sheppard
- Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
| | - Frances K. Wiseman
- Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
| | - Aarti Ruparelia
- Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
| | - Victor L. J. Tybulewicz
- Division of Immune Cell Biology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK
| | - Elizabeth M. C. Fisher
- Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
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27
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The influence of sex-linked genetic mechanisms on attention and impulsivity. Biol Psychol 2011; 89:1-13. [PMID: 21983394 PMCID: PMC3245859 DOI: 10.1016/j.biopsycho.2011.09.011] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2011] [Revised: 09/20/2011] [Accepted: 09/20/2011] [Indexed: 12/28/2022]
Abstract
It is now generally agreed that there are inherent sex differences in healthy individuals across a number of neurobiological domains (including brain structure, neurochemistry, and cognition). Moreover, there is a burgeoning body of evidence highlighting sex differences within neuropsychiatric populations (in terms of the rates of incidence, clinical features/progression, neurobiology and pathology). Here, we consider the extent to which attention and impulsivity are sexually dimorphic in healthy populations and the extent to which sex might modulate the expression of disorders characterised by abnormalities in attention and/or impulsivity such as attention deficit hyperactivity disorder (ADHD), autism and addiction. We then discuss general genetic mechanisms that might underlie sex differences in attention and impulsivity before focussing on specific positional and functional candidate sex-linked genes that are likely to influence these cognitive processes. Identifying novel sex-modulated molecular targets should ultimately enable us to develop more effective therapies in disorders associated with attentional/impulsive dysfunction.
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28
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Rivet TT, Matson JL. Review of gender differences in core symptomatology in autism spectrum disorders. RESEARCH IN AUTISM SPECTRUM DISORDERS 2011; 5:957-976. [DOI: 10.1016/j.rasd.2010.12.003] [Citation(s) in RCA: 139] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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29
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Hochberg Z, Feil R, Constancia M, Fraga M, Junien C, Carel JC, Boileau P, Le Bouc Y, Deal CL, Lillycrop K, Scharfmann R, Sheppard A, Skinner M, Szyf M, Waterland RA, Waxman DJ, Whitelaw E, Ong K, Albertsson-Wikland K. Child health, developmental plasticity, and epigenetic programming. Endocr Rev 2011; 32:159-224. [PMID: 20971919 PMCID: PMC3365792 DOI: 10.1210/er.2009-0039] [Citation(s) in RCA: 419] [Impact Index Per Article: 29.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2009] [Accepted: 08/27/2010] [Indexed: 11/19/2022]
Abstract
Plasticity in developmental programming has evolved in order to provide the best chances of survival and reproductive success to the organism under changing environments. Environmental conditions that are experienced in early life can profoundly influence human biology and long-term health. Developmental origins of health and disease and life-history transitions are purported to use placental, nutritional, and endocrine cues for setting long-term biological, mental, and behavioral strategies in response to local ecological and/or social conditions. The window of developmental plasticity extends from preconception to early childhood and involves epigenetic responses to environmental changes, which exert their effects during life-history phase transitions. These epigenetic responses influence development, cell- and tissue-specific gene expression, and sexual dimorphism, and, in exceptional cases, could be transmitted transgenerationally. Translational epigenetic research in child health is a reiterative process that ranges from research in the basic sciences, preclinical research, and pediatric clinical research. Identifying the epigenetic consequences of fetal programming creates potential applications in clinical practice: the development of epigenetic biomarkers for early diagnosis of disease, the ability to identify susceptible individuals at risk for adult diseases, and the development of novel preventive and curative measures that are based on diet and/or novel epigenetic drugs.
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Affiliation(s)
- Z Hochberg
- Rambam Medical Center, Rappaport Faculty of Medicine and Research Institute, Technion–Israel Institute of Technology, Haifa, Israel.
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30
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Kopsida E, Mikaelsson MA, Davies W. The role of imprinted genes in mediating susceptibility to neuropsychiatric disorders. Horm Behav 2011; 59:375-82. [PMID: 20403360 DOI: 10.1016/j.yhbeh.2010.04.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2010] [Revised: 03/31/2010] [Accepted: 04/09/2010] [Indexed: 11/25/2022]
Abstract
Imprinted genes, which are thought to comprise <1% of the mammalian genome, are defined by their parent-of-origin specific monoallelic expression arising as a consequence of differential epigenetic marking of alleles in the paternal and maternal germlines. Such genes are highly represented in the brain and placental transcriptomes, and have been shown to exert significant influence on fundamental developmental processes in these organs. Converging evidence from work in man and animal models has shown that imprinted genes can influence a variety of brain and behavioral endophenotypes. In this article, we review the current evidence that imprinted gene dysfunction is associated with vulnerability to several common psychiatric disorders. We also discuss how studying imprinted gene (dys)function may provide mechanistic insights into two important areas in modern psychiatry: first, how environmental factors (especially in utero) interact with genetic liability via epigenetic mechanisms to predispose to later mental illness, and second, the molecular underpinnings of sex-specific vulnerability to psychiatric disorders.
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31
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Dye CA, El Shawa H, Huffman KJ. A lifespan analysis of intraneocortical connections and gene expression in the mouse II. ACTA ACUST UNITED AC 2010; 21:1331-50. [PMID: 21060113 DOI: 10.1093/cercor/bhq213] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
The mammalian neocortex contains an intricate processing network of multiple sensory and motor areas that allows the animal to engage in complex behaviors. These anatomically and functionally unique areas and their distinct connections arise during early development, through a process termed arealization. Both intrinsic, activity-independent and extrinsic, activity-dependent mechanisms drive arealization, much of which occurs during the areal patterning period (APP) from late embryogenesis to early postnatal life. How areal boundaries and their connections develop and change from infancy to adulthood is not known. Additionally, the adult patterns of sensory and motor ipsilateral intraneocortical connections (INCs) have not been thoroughly characterized in the mouse. In this report and its companion (I), we present the first lifespan analysis of ipsilateral INCs among multiple sensory and motor regions in mouse. We describe the neocortical expression patterns of several developmentally regulated genes that are of central importance to studies investigating the molecular regulation of arealization, from postnatal day (P) 6 to P50. In this study, we correlate the boundaries of gene expression patterns with developing areal boundaries across a lifespan, in order to better understand the nature of gene-areal relationships from early postnatal life to adulthood.
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Affiliation(s)
- Catherine A Dye
- Department of Psychology and Interdepartmental Neuroscience Program, University of California-Riverside, 900 University Avenue, Riverside, CA 92521, USA
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32
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Liu PY, Erkkila K, Lue Y, Jentsch JD, Schwarcz MD, Abuyounes D, Hikim AS, Wang C, Lee PWN, Swerdloff RS. Genetic, hormonal, and metabolomic influences on social behavior and sex preference of XXY mice. Am J Physiol Endocrinol Metab 2010; 299:E446-55. [PMID: 20570823 PMCID: PMC2944286 DOI: 10.1152/ajpendo.00085.2010] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
XXY men (Klinefelter syndrome) are testosterone deficient, socially isolated, exhibit impaired gender identity, and may experience more homosexual behaviors. Here, we characterize social behaviors in a validated XXY mouse model to understand mechanisms. Sociability and gender preference were assessed by three-chambered choice tasks before and after castration and after testosterone replacement. Metabolomic activities of brain and blood were quantified through fractional synthesis rates of palmitate and ribose (GC-MS). XXY mice exhibit greater sociability than XY littermates, particularly for male mice. The differences in sociability disappear after matching androgen exposure. Intact XXY, compared with XY, mice prefer male mice odors when the alternatives are ovariectomized female mice odors, but they prefer estrous over male mice odors, suggesting that preference for male mice may be due to social, not sexual, cues. Castration followed by testosterone treatment essentially remove these preferences. Fractional synthesis rates of palmitate are higher in the hypothalamus, amygdala, and hippocampus of XXY compared with XY mice but not with ribose in these brain regions or palmitate in blood. Androgen ablation in XY mice increases fractional synthesis rates of fatty acids in the brain to levels indistinguishable from those in XXY mice. We conclude that intact XXY mice exhibit increased sociability, differences in gender preference for mice and their odors are due to social rather than sexual cues and, these differences are mostly related to androgen deficiency rather than genetics. Specific metabolic changes in brain lipids, which are also regulated by androgens, are observed in brain regions that are involved in these behaviors.
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Affiliation(s)
- Peter Y Liu
- Department of Medicine, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, California, USA.
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33
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Mizuno K, Giese KP. Towards a molecular understanding of sex differences in memory formation. Trends Neurosci 2010; 33:285-91. [PMID: 20356635 DOI: 10.1016/j.tins.2010.03.001] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2009] [Revised: 03/04/2010] [Accepted: 03/04/2010] [Indexed: 11/29/2022]
Abstract
Sex differences exist in brain function and behavior. However, the underlying molecular mechanisms are only beginning to emerge. Recent studies in rodents have revealed molecular mechanisms underlying sex differences in memory formation. It is becoming clear that sex differences are not simply reflective of differences in sex hormones, but also reflect distinctions in synaptic signaling mechanisms including the role of synaptic kinases. Furthermore, there are sex differences in the activation of transcription factors and gene transcription during memory formation. This review discusses emerging evidence in the field and how these findings are providing a first step towards a molecular understanding of how sex differences impact on memory formation both in health and disease.
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Affiliation(s)
- Keiko Mizuno
- King's College London, Institute of Psychiatry, Department of Neuroscience, London SE5 9NU, UK.
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Yang F, Babak T, Shendure J, Disteche CM. Global survey of escape from X inactivation by RNA-sequencing in mouse. Genome Res 2010; 20:614-22. [PMID: 20363980 DOI: 10.1101/gr.103200.109] [Citation(s) in RCA: 276] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
X inactivation equalizes the dosage of gene expression between the sexes, but some genes escape silencing and are thus expressed from both alleles in females. To survey X inactivation and escape in mouse, we performed RNA sequencing in Mus musculus x Mus spretus cells with complete skewing of X inactivation, relying on expression of single nucleotide polymorphisms to discriminate allelic origin. Thirteen of 393 (3.3%) mouse genes had significant expression from the inactive X, including eight novel escape genes. We estimate that mice have significantly fewer escape genes compared with humans. Furthermore, escape genes did not cluster in mouse, unlike the large escape domains in human, suggesting that expression is controlled at the level of individual genes. Our findings are consistent with the striking differences in phenotypes between female mice and women with a single X chromosome--a near normal phenotype in mice versus Turner syndrome and multiple abnormalities in humans. We found that escape genes are marked by the absence of trimethylation at lysine 27 of histone H3, a chromatin modification associated with genes subject to X inactivation. Furthermore, this epigenetic mark is developmentally regulated for some mouse genes.
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Affiliation(s)
- Fan Yang
- Department of Pathology, University of Washington, Seattle, Washington 98195, USA
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35
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Kernohan KD, Jiang Y, Tremblay DC, Bonvissuto AC, Eubanks JH, Mann MRW, Bérubé NG. ATRX partners with cohesin and MeCP2 and contributes to developmental silencing of imprinted genes in the brain. Epigenomics 2010; 2:743-63. [PMID: 20159591 DOI: 10.2217/epi.10.61] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Human developmental disorders caused by chromatin dysfunction often display overlapping clinical manifestations, such as cognitive deficits, but the underlying molecular links are poorly defined. Here, we show that ATRX, MeCP2, and cohesin, chromatin regulators implicated in ATR-X, RTT, and CdLS syndromes, respectively, interact in the brain and colocalize at the H19 imprinting control region (ICR) with preferential binding on the maternal allele. Importantly, we show that ATRX loss of function alters enrichment of cohesin, CTCF, and histone modifications at the H19 ICR, without affecting DNA methylation on the paternal allele. ATRX also affects cohesin, CTCF, and MeCP2 occupancy within the Gtl2/Dlk1 imprinted domain. Finally, we show that loss of ATRX interferes with the postnatal silencing of the maternal H19 gene along with a larger network of imprinted genes. We propose that ATRX, cohesin, and MeCP2 cooperate to silence a subset of imprinted genes in the postnatal mouse brain.
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Affiliation(s)
- Kristin D Kernohan
- Department of Paediatrics, 800 Commissioners Road East, London, ON N6C 2V5, Canada
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36
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Burnett AC, Reutens DC, Wood AG. Social cognition in Turner’s Syndrome. J Clin Neurosci 2010; 17:283-6. [DOI: 10.1016/j.jocn.2009.09.006] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2009] [Revised: 07/20/2009] [Accepted: 09/24/2009] [Indexed: 11/30/2022]
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Lopes AM, Burgoyne PS, Ojarikre A, Bauer J, Sargent CA, Amorim A, Affara NA. Transcriptional changes in response to X chromosome dosage in the mouse: implications for X inactivation and the molecular basis of Turner Syndrome. BMC Genomics 2010; 11:82. [PMID: 20122165 PMCID: PMC2837040 DOI: 10.1186/1471-2164-11-82] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2009] [Accepted: 02/01/2010] [Indexed: 11/12/2022] Open
Abstract
Background X monosomic mice (39,XO) have a remarkably mild phenotype when compared to women with Turner syndrome (45,XO). The generally accepted hypothesis to explain this discrepancy is that the number of genes on the mouse X chromosome which escape X inactivation, and thus are expressed at higher levels in females, is very small. However this hypothesis has never been tested and only a small number of genes have been assayed for their X-inactivation status in the mouse. We performed a global expression analysis in four somatic tissues (brain, liver, kidney and muscle) of adult 40,XX and 39,XO mice using the Illumina Mouse WG-6 v1_1 Expression BeadChip and an extensive validation by quantitative real time PCR, in order to identify which genes are expressed from both X chromosomes. Results We identified several genes on the X chromosome which are overexpressed in XX females, including those previously reported as escaping X inactivation, as well as new candidates. However, the results obtained by microarray and qPCR were not fully concordant, illustrating the difficulty in ascertaining modest fold changes, such as those expected for genes escaping X inactivation. Remarkably, considerable variation was observed between tissues, suggesting that inactivation patterns may be tissue-dependent. Our analysis also exposed several autosomal genes involved in mitochondrial metabolism and in protein translation which are differentially expressed between XX and XO mice, revealing secondary transcriptional changes to the alteration in X chromosome dosage. Conclusions Our results support the prediction that the mouse inactive X chromosome is largely silent, while providing a list of the genes potentially escaping X inactivation in rodents. Although the lower expression of X-linked genes in XO mice may not be relevant in the particular tissues/systems which are affected in human X chromosome monosomy, genes deregulated in XO mice are good candidates for further study in an involvement in Turner Syndrome phenotype.
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Affiliation(s)
- Alexandra M Lopes
- IPATIMUP, Instituto de Patologia e Imunologia Molecular da Universidade do Porto, 4200-465 Porto, Portugal.
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38
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Crespi B, Summers K, Dorus S. Genomic sister-disorders of neurodevelopment: an evolutionary approach. Evol Appl 2009; 2:81-100. [PMID: 25567849 PMCID: PMC3352408 DOI: 10.1111/j.1752-4571.2008.00056.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2008] [Accepted: 11/26/2008] [Indexed: 02/06/2023] Open
Abstract
Genomic sister-disorders are defined here as diseases mediated by duplications versus deletions of the same region. Such disorders can provide unique information concerning the genomic underpinnings of human neurodevelopment because effects of diametric variation in gene copy number on cognitive and behavioral phenotypes can be inferred. We describe evidence from the literature on deletions versus duplications for the regions underlying the best-known human neurogenetic sister-disorders, including Williams syndrome, Velocardiofacial syndrome, and Smith-Magenis syndrome, as well as the X-chromosomal conditions Klinefelter and Turner syndromes. These data suggest that diametric copy-number alterations can, like diametric alterations to imprinted genes, generate contrasting phenotypes associated with autistic-spectrum and psychotic-spectrum conditions. Genomically based perturbations to the development of the human social brain are thus apparently mediated to a notable degree by effects of variation in gene copy number. We also conducted the first analyses of positive selection for genes in the regions affected by these disorders. We found evidence consistent with adaptive evolution of protein-coding genes, or selective sweeps, for three of the four sets of sister-syndromes analyzed. These studies of selection facilitate identification of candidate genes for the phenotypes observed and lend a novel evolutionary dimension to the analysis of human cognitive architecture and neurogenetic disorders.
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Affiliation(s)
- Bernard Crespi
- Department of Biosciences, Simon Fraser University Burnaby, BC, Canada
| | - Kyle Summers
- Department of Biology, East Carolina University Greenville, NC, USA
| | - Steve Dorus
- Department of Biology and Biochemistry, University of Bath Bath, UK
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39
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Kopsida E, Stergiakouli E, Lynn PM, Wilkinson LS, Davies W. The Role of the Y Chromosome in Brain Function. OPEN NEUROENDOCRINOLOGY JOURNAL (ONLINE) 2009; 2:20-30. [PMID: 20396406 PMCID: PMC2854822 DOI: 10.2174/1876528900902010020] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
In mammals, sex differences are evident in many aspects of brain development, brain function and behaviour. Ultimately, such differences must arise from the differential sex chromosome complements in males and females: males inherit a single X chromosome and a Y chromosome, whilst females inherit two X chromosomes. One possible mechanism for sexual differentiation of the brain is via male-limited expression of genes on the small Y chromosome. Many Y-linked genes have been implicated in the development of the testes, and therefore could theoretically contribute to sexual differentiation of the brain indirectly, through influencing gonadal hormone production. Alternatively, Y-linked genes that are expressed in the brain could directly influence neural masculinisation. The present paper reviews evidence from human genetic studies and animal models for Y-linked effects (both direct and indirect) on neurodevelopment, brain function and behaviour. Besides enhancing our knowledge of the mechanisms underlying mammalian neural sexual differentiation, studies geared towards understanding the role of the Y chromosome in brain function will help to elucidate the molecular basis of sex-biased neuropsychiatric disorders, allowing for more selective sex-specific therapies.
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Affiliation(s)
- Eleni Kopsida
- Henry Wellcome Building, School of Medicine, Heath Park Site, Cardiff University, UK
- MRC Centre for Neuropsychiatric Genetics and Genomics and Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, UK
| | - Evangelia Stergiakouli
- MRC Centre for Neuropsychiatric Genetics and Genomics and Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, UK
| | - Phoebe M. Lynn
- Henry Wellcome Building, School of Medicine, Heath Park Site, Cardiff University, UK
- MRC Centre for Neuropsychiatric Genetics and Genomics and Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, UK
| | - Lawrence S. Wilkinson
- Henry Wellcome Building, School of Medicine, Heath Park Site, Cardiff University, UK
- MRC Centre for Neuropsychiatric Genetics and Genomics and Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, UK
| | - William Davies
- Henry Wellcome Building, School of Medicine, Heath Park Site, Cardiff University, UK
- MRC Centre for Neuropsychiatric Genetics and Genomics and Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, UK
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40
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Abstract
AbstractThe commentaries on our target article, “Psychosis and Autism as Diametrical Disorders of the Social Brain,” reflect the multidisciplinary yet highly fragmented state of current studies of human social cognition. Progress in our understanding of the human social brain must come from studies that integrate across diverse analytic levels, using conceptual frameworks grounded in evolutionary biology.
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Crespi B. Turner syndrome and the evolution of human sexual dimorphism. Evol Appl 2008; 1:449-61. [PMID: 25567727 PMCID: PMC3352375 DOI: 10.1111/j.1752-4571.2008.00017.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2007] [Accepted: 01/17/2008] [Indexed: 12/17/2022] Open
Abstract
Turner syndrome is caused by loss of all or part of an X chromosome in females. A series of recent studies has characterized phenotypic differences between Turner females retaining the intact maternally inherited versus paternally inherited X chromosome, which have been interpreted as evidence for effects of X-linked imprinted genes. In this study I demonstrate that the differences between Turner females with a maternal X and a paternal X broadly parallel the differences between males and normal females for a large suite of traits, including lipid profile and visceral fat, response to growth hormone, sensorineural hearing loss, congenital heart and kidney malformations, neuroanatomy (sizes of the cerebellum, hippocampus, caudate nuclei and superior temporal gyrus), and aspects of cognition. This pattern indicates that diverse aspects of human sex differences are mediated in part by X-linked genes, via genomic imprinting of such genes, higher rates of mosaicism in Turner females with an intact X chromosome of paternal origin, karyotypic differences between Turner females with a maternal versus paternal X chromosome, or some combination of these phenomena. Determining the relative contributions of genomic imprinting, karyotype and mosaicism to variation in Turner syndrome phenotypes has important implications for both clinical treatment of individuals with this syndrome, and hypotheses for the evolution and development of human sexual dimorphism.
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Affiliation(s)
- Bernard Crespi
- Department of Biosciences, Simon Fraser University Burnaby, BC, Canada
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