• basement membrane
• chondroitin sulfate
• dystroglycan
• glycosaminoglycans
• heparan sulfate
• human disease
• keratan sulfate
• neural networks
• neurophysiology
• synaptic stabilization

• Glycosaminoglycans/metabolism
• Glycosaminoglycans/chemistry
• Humans
• Animals
• Extracellular Matrix/metabolism
• Neurons/metabolism
• Synapses/metabolism
• Proteoglycans/metabolism

• no grant number Melrose Personal Research Fund, Sydney, Australia

• C3H10T1/2
• Heparin
• High-throughput screening
• SAG
• Sonic hedgehog

• Hedgehog Proteins/metabolism
• Hedgehog Proteins/antagonists & inhibitors
• Heparin/metabolism
• Heparin/chemistry
• Animals
• Small Molecule Libraries/pharmacology
• Small Molecule Libraries/chemistry
• Mice
• Humans
• Protein Binding
• Signal Transduction/drug effects
• Cell Line
• Zinc Finger Protein GLI1/metabolism
• Zinc Finger Protein GLI1/antagonists & inhibitors

• R01 MD017405 NIMHD NIH HHS
• R15 CA159209 NCI NIH HHS
• U54 AA030451 NIAAA NIH HHS
• U54 MD012392 NIMHD NIH HHS

• hedgehog
• sinonasal adenocarcinoma
• tumor–stroma interaction

• Humans
• Hedgehog Proteins/metabolism
• Hedgehog Proteins/genetics
• Adenocarcinoma/metabolism
• Adenocarcinoma/pathology
• Signal Transduction
• Male
• Female
• Immunohistochemistry
• Zinc Finger Protein Gli2/metabolism
• Zinc Finger Protein Gli2/genetics
• Middle Aged
• Pilot Projects
• Aged
• Patched-1 Receptor/metabolism
• Patched-1 Receptor/genetics
• Zinc Finger Protein GLI1/metabolism
• Zinc Finger Protein GLI1/genetics
• Zinc Finger Protein Gli3/metabolism
• Zinc Finger Protein Gli3/genetics
• Paranasal Sinus Neoplasms/metabolism
• Paranasal Sinus Neoplasms/pathology
• Adult
• Gene Expression Regulation, Neoplastic
• Nerve Tissue Proteins
• Nuclear Proteins

• HrZZ-IP-2018-01-4889 Croatian Science Foundation
• donation Croatian Society for Head and Neck Tumors

• T cell
• alloimmune
• hedgehog
• humanized model mouse
• ischemia-reperfusion (I/R) injury

• Mice
• Animals
• Humans
• Cytokines
• Hedgehog Proteins
• Reperfusion Injury/metabolism
• T-Lymphocytes, Helper-Inducer/metabolism
• Organ Transplantation

• I01 BX005117 BLRD VA
• P30 DK034989 NIDDK NIH HHS
• R01 HL141137 NHLBI NIH HHS
• R21 AI178582 NIAID NIH HHS

• cell biology
• cancer

• Adult
• Female
• Pregnancy
• Humans
• Hedgehog Proteins/genetics
• Homeostasis/genetics
• Neoplasms/drug therapy
• Neoplasms/genetics
• Signal Transduction/genetics
• Cell Differentiation

• National Natural Science Foundation of China (National Science Foundation of China)
• China Association for Science and Technology (China Association for Science & Technology)

• Animals
• Humans
• Mice
• Endothelial Cells/metabolism
• Hedgehog Proteins/genetics
• Hedgehog Proteins/metabolism
• Inflammasomes/genetics
• Inflammasomes/metabolism
• Inflammation/genetics
• Inflammation/metabolism
• Mice, Inbred C57BL
• NLR Family, Pyrin Domain-Containing 3 Protein/genetics
• NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
• T-Lymphocytes/metabolism
• Membrane Proteins/metabolism
• Intracellular Signaling Peptides and Proteins/metabolism

• R01 HL051014 NHLBI NIH HHS
• I01 BX005117 BLRD VA
• R21 AI178582 NIAID NIH HHS
• MR/S037764/1 Medical Research Council
• R01 HL141137 NHLBI NIH HHS
• R00 HL125895 NHLBI NIH HHS

• Chronic rhinosinusitis with nasal polyps (CRSwNP)
• Eosinophils (EOS)
• Epithelial–mesenchymal transition (EMT)
• Hedgehog (Hh)
• PTCH
• Proliferation

• Lhx2
• Sonic Hedgehog
• development
• developmental biology
• genetics
• genomics
• mouse
• retina
• signaling

• Mice
• Animals
• Hedgehog Proteins
• Neurogenesis/genetics
• Retina
• Signal Transduction
• Transcription Factors
• LIM-Homeodomain Proteins/genetics

• R00 HD087532 NICHD NIH HHS
• R01 EY013760 NEI NIH HHS
• R01 AG020560 NIA NIH HHS
• R01 EY031685 NEI NIH HHS
• P30 EY014800 NEI NIH HHS
• P30 EY008126 NEI NIH HHS
• DP2 HD108777 NICHD NIH HHS
• National Eye Institute
• Eunice Kennedy Shriver National Institute of Child Health and Human Development
• Research to Prevent Blindness

• Platynereis dumerilii
• Pygopsio elegans
• Spiralia
• annelids
• hedgehog signaling
• molecular evolution
• pathway
• transcriptome analysis

• Animals
• Mice
• Hedgehog Proteins/genetics
• Hedgehog Proteins/metabolism
• Phylogeny
• Annelida/genetics
• Vertebrates/metabolism
• Polychaeta/genetics
• Polychaeta/metabolism
• Drosophila/metabolism

TALPID3/KIAA0586 is an evolutionary conserved protein, which plays an essential role in protein trafficking. Its role during gastrointestinal (GI) and enteric nervous system (ENS) development has not been studied previously. Here, we analyzed chicken, mouse and human embryonic GI tissues with TALPID3 mutations. The GI tract of TALPID3 chicken embryos was shortened and malformed. Histologically, the gut smooth muscle was mispatterned and enteric neural crest cells were scattered throughout the gut wall. Analysis of the Hedgehog pathway and gut extracellular matrix provided causative reasons for these defects. Interestingly, chicken intra-species grafting experiments and a conditional knockout mouse model showed that ENS formation did not require TALPID3, but was dependent on correct environmental cues. Surprisingly, the lack of TALPID3 in enteric neural crest cells (ENCC) affected smooth muscle and epithelial development in a non-cell-autonomous manner. Analysis of human gut fetal tissues with a KIAA0586 mutation showed strikingly similar findings compared to the animal models demonstrating conservation of TALPID3 and its necessary role in human GI tract development and patterning.

• Joubert syndrome
• KIAA0586
• Sonic Hedgehog
• TALPID3
• enteric nervous system
• gastrointestinal tract
• neural crest cell
• short-rib polydactyly syndrome

The liver has remarkable regenerative potential, with the capacity to regenerate after 75% hepatectomy in humans and up to 90% hepatectomy in some rodent models, enabling it to meet the challenge of diverse injury types, including physical trauma, infection, inflammatory processes, direct toxicity, and immunological insults. Current understanding of liver regeneration is based largely on animal research, historically in large animals, and more recently in rodents and zebrafish, which provide powerful genetic manipulation experimental tools. Whilst immensely valuable, these models have limitations in extrapolation to the human situation. In vitro models have evolved from 2-dimensional culture to complex 3 dimensional organoids, but also have shortcomings in replicating the complex hepatic micro-anatomical and physiological milieu. The process of liver regeneration is only partially understood and characterized by layers of complexity. Liver regeneration is triggered and controlled by a multitude of mitogens acting in autocrine, paracrine, and endocrine ways, with much redundancy and cross-talk between biochemical pathways. The regenerative response is variable, involving both hypertrophy and true proliferative hyperplasia, which is itself variable, including both cellular phenotypic fidelity and cellular trans-differentiation, according to the type of injury. Complex interactions occur between parenchymal and non-parenchymal cells, and regeneration is affected by the status of the liver parenchyma, with differences between healthy and diseased liver. Finally, the process of termination of liver regeneration is even less well understood than its triggers. The complexity of liver regeneration biology combined with limited understanding has restricted specific clinical interventions to enhance liver regeneration. Moreover, manipulating the fundamental biochemical pathways involved would require cautious assessment, for fear of unintended consequences. Nevertheless, current knowledge provides guiding principles for strategies to optimise liver regeneration potential.

• Liver
• Liver regeneration potential
• Regeneration biology
• Tumour
• Therapies

• Cartilage tumor
• Endochondral ossification
• Growth plate
• Osteochondroma
• Retinoids

• Animals
• Bone Neoplasms/etiology
• Bone Neoplasms/pathology
• Disease Models, Animal
• Humans
• Mice
• Osteochondroma/etiology
• Osteochondroma/pathology
• Retinoids/metabolism
• Signal Transduction/physiology

• R01 AR072713 NIAMS NIH HHS
• R01 AR073181 NIAMS NIH HHS

• Hh signaling pathway
• giant cell tumor of bone
• primary cilium
• ultrastructural study

The Hedgehog pathway is a fundamental signaling pathway in organogenesis. The expression patterns of the ligand Sonic Hedgehog (Shh) and key pathway components have been studied in many tissues but direct spatial comparisons across tissues with different cell compositions and structural organization are not common and could reveal tissue-specific differences in pathway dynamics.

We directly compared the expression characteristics of Shh, and four genes with functional roles in signaling and whose expression levels serve as readouts of pathway activity in multiple tissues of the embryonic mouse head at embryonic day 15.5 by serial in situ hybridization. The four readout genes were the positive feedback regulator Gli1, and three negative feedback regulators, Patched1, Patched2, and Hedgehog Interacting Protein. While the relative abundance of Gli1 was similar across tissues, the relative expression levels and spatial distribution of Shh and the negative feedback regulators differed, suggesting that feedback regulation of hedgehog signaling is context dependent. This comparative analysis offers insight into how consistent pathway activity could be achieved in tissues with different morphologies and characteristics of ligand expression.

The online version contains supplementary material available at 10.1186/s13104-021-05714-5.

• Embryonic day 15.5
• Eyelid
• Gene expression
• Gli1
• Hair follicle
• Hedgehog interacting protein
• Molar
• Palatal rugae
• Patched
• Retina
• Sonic hedgehog

The Hedgehog/GLI (Hh/GLI) pathway plays a major role during development and it is commonly dysregulated in many diseases, including cancer. This highly concerted series of ligands, receptors, cytoplasmic signaling molecules, transcription factors, and co-regulators is involved in regulating the biological functions controlled by this pathway. Activation of Hh/GLI in cancer is most often through a non-canonical method of activation, independent of ligand binding. This review is intended to summarize our current understanding of the Hh/GLI signaling, non-canonical mechanisms of pathway activation, its implication in disease, and the current therapeutic strategies targeting this cascade.

The Hh/GLI signaling pathway was originally discovered in Drosophila as a major regulator of segment patterning in development. This pathway consists of a series of ligands (Shh, Ihh, and Dhh), transmembrane receptors (Ptch1 and Ptch2), transcription factors (GLI1–3), and signaling regulators (SMO, HHIP, SUFU, PKA, CK1, GSK3β, etc.) that work in concert to repress (Ptch1, Ptch2, SUFU, PKA, CK1, GSK3β) or activate (Shh, Ihh, Dhh, SMO, GLI1–3) the signaling cascade. Not long after the initial discovery, dysregulation of the Hh/GLI signaling pathway was implicated in human disease. Activation of this signaling pathway is observed in many types of cancer, including basal cell carcinoma, medulloblastoma, colorectal, prostate, pancreatic, and many more. Most often, the activation of the Hh/GLI pathway in cancer occurs through a ligand-independent mechanism. However, in benign disease, this activation is mostly ligand-dependent. The upstream signaling component of the receptor complex, SMO, is bypassed, and the GLI family of transcription factors can be activated regardless of ligand binding. Additional mechanisms of pathway activation exist whereby the entirety of the downstream signaling pathway is bypassed, and PTCH1 promotes cell cycle progression and prevents caspase-mediated apoptosis. Throughout this review, we summarize each component of the signaling cascade, non-canonical modes of pathway activation, and the implications in human disease, including cancer.

• GLI
• Hh pathway inhibitors
• SUFU
• cancer
• canonical and non-canonical activation
• hedgehog

• androgen
• cholesterol
• disorders of cholesterol synthesis
• disorders of sex development
• hedgehog signaling
• male sex differentiation

• Androgens/biosynthesis
• Animals
• Cholesterol/biosynthesis
• Cholesterol/physiology
• Disorders of Sex Development
• Fetal Development/physiology
• Fetus/metabolism
• Hedgehog Proteins/metabolism
• Humans
• Leydig Cells/physiology
• Male
• Sex Differentiation/physiology
• Signal Transduction/physiology
• Testis/embryology
• Testis/metabolism

• R01 HD090660 NICHD NIH HHS
• National Institutes of Health

• Sonic hedgehog
• astrocyte
• glia
• inflammation
• neuron–astrocyte communication

Gene regulatory divergence is thought to play a central role in determining human-specific traits. However, our ability to link divergent regulation to divergent phenotypes is limited. Here, we utilized human-chimpanzee hybrid induced pluripotent stem cells to study gene expression separating these species. The tetraploid hybrid cells allowed us to separate cis- from trans-regulatory effects, and to control for non-genetic confounding factors. We differentiated these cells into cranial neural crest cells (CNCCs), the primary cell type giving rise to the face. We discovered evidence of lineage-specific selection on the hedgehog signaling pathway, including a human-specific 6-fold down-regulation of EVC2 (LIMBIN), a key hedgehog gene. Inducing a similar down-regulation of EVC2 substantially reduced hedgehog signaling output. Mice and humans lacking functional EVC2 show striking phenotypic parallels to human-chimpanzee craniofacial differences, suggesting that the regulatory divergence of hedgehog signaling may have contributed to the unique craniofacial morphology of humans.

• Bladder cancer
• Epithelial–mesenchymal transition
• Hedeghog signalling pathway
• Primary cilia
• Transmission electron microscopy
• Ultrastructure

• Cilia/metabolism
• Cilia/pathology
• Humans
• Urinary Bladder Neoplasms/metabolism
• Urinary Bladder Neoplasms/pathology

• Astrocyte
• Gli1
• Glia
• Neuron-astrocyte communication
• Sonic hedgehog

• Animals
• Astrocytes/metabolism
• Brain/growth & development
• Brain/metabolism
• Cell Differentiation/genetics
• Hedgehog Proteins/genetics
• Humans
• Nervous System/growth & development
• Nervous System/metabolism
• Nervous System/pathology
• Neurogenesis/genetics
• Neurons/metabolism
• Neurons/pathology
• Signal Transduction/genetics

• R01 NS096100 NINDS NIH HHS
• R21 NS116664 NINDS NIH HHS
• R01NS096100 NINDS NIH HHS
• National Institute of Neurological Disorders and Stroke

• Cancer
• Cancer stem cells
• Cell proliferation/differentiation
• Cell survival
• Dual-specificity tyrosine-regulated kinase 1B
• Hedgehog
• Minibrain-related kinase
• Quiescence
• Stem cells

• cytokines
• endothelial cells
• endothelium
• hedgehogs
• therapeutics

• Alcohol
• Bacteremia
• Hematopoietic Stem Cells
• Host Response
• Sonic Hedgehog

• Alcoholic Intoxication/complications
• Alcoholic Intoxication/metabolism
• Animals
• Bacteremia/metabolism
• Flow Cytometry
• Hedgehog Proteins/metabolism
• Hematopoietic Stem Cells/drug effects
• Hematopoietic Stem Cells/metabolism
• Hematopoietic Stem Cells/physiology
• MAP Kinase Signaling System/drug effects
• Male
• Mice
• Mice, Inbred BALB C
• Signal Transduction/drug effects
• Zinc Finger Protein GLI1/metabolism

• R01 GM132449 NIGMS NIH HHS
• R01 AA022816 NIAAA NIH HHS

• RP5-1092A11.2
• benign esophagitis
• early-stage esophageal squamous cell carcinoma
• exosomal lncRNAs
• functional assay

• GIST
• Hedgehog signalling
• Immunohistochemistry
• Primary cilium
• Ultrastructure

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-associated mortality worldwide. Hepatocarcinogenesis involves numerous interlinked factors and processes, including the Sonic hedgehog (Shh) signaling pathway, which participates in the carcinogenesis, progression, invasiveness, recurrence and cancer stem cell maintenance of HCC. The Shh signaling pathway is activated by ligands that bind to their receptor protein, Protein patched homolog (Ptch). The process of Shh ligand binding to Ptch weakens the inhibition of smoothened homolog (SMO) and activates signal transduction via glioma-associated oncogene homolog (Gli) transcription factors. The overexpression of Shh pathway molecules, including Shh, Ptch-1, Gli and SMO has been indicated in patients with HCC. It has also been suggested that the Shh signaling pathway exhibits cross-talk between numerous other signaling pathways. The inactivation of the Shh signaling pathway reduces HCC growth, increases radio-sensitivity and increases the beneficial effect of chemotherapy in HCC treatment. Therefore, inhibition of the Shh pathway may be an effective target therapy that can be used in the treatment of HCC.

• cancer stem cells
• hepatocellular carcinoma
• recurrence
• sonic hedgehog signaling pathway

• Central nervous system (CNS) and skeletal system development
• Glycosaminoglycans (GAGs)
• Heparan sulfate proteoglycans (HSPGs)
• Lysosomal storage diseases (LSDs)
• Mucopolysaccharidoses (MPSs)

Here we investigate the function of Hedgehog (Hh) signaling in thymic γδ T-cell maturation and subset differentiation. Analysis of Hh mutants showed that Hh signaling promotes γδ T-cell development in the thymus and influences γδ T-cell effector subset distribution. Hh-mediated transcription in thymic γδ cells increased γδ T-cell number, and promoted their maturation and increased the γδNKT subset, whereas inhibition of Hh-mediated transcription reduced the thymic γδ T-cell population and increased expression of many genes that are normally down-regulated during γδ T-cell maturation. These changes were also evident in spleen, where increased Hh signaling increased γδNKT cells, but reduced CD27-CD44+ and Vγ2+ populations. Systemic in vivo pharmacological Smoothened-inhibition reduced γδ T-cell and γδNKT cells in the thymus, and also reduced splenic γδ T-cell and γδNKT populations, indicating that Hh signaling also influences homeostasis of peripheral γδ T-cell populations. Taken together our data indicate that Sonic Hedgehog is an important determinant of γδ T-cell effector subset differentiation.

• Hedgehog
• Shh
• Smoothened
• thymus
• γδ T-cell
• γδNKT

Hedgehog (Hh) proteins regulate development and tissue homeostasis, but their role in atopic dermatitis (AD) remains unknown. We found that on induction of mouse AD, Sonic Hedgehog (Shh) expression in skin and Hh pathway action in skin T cells were increased. Shh signaling reduced AD pathology and the levels of Shh expression determined disease severity. Hh-mediated transcription in skin T cells in AD-induced mice increased Treg populations and their suppressive function through increased active transforming growth factor–β (TGF-β) in Treg signaling to skin T effector populations to reduce disease progression and pathology. RNA sequencing of skin CD4⁺ T cells from AD-induced mice demonstrated that Hh signaling increased expression of immunoregulatory genes and reduced expression of inflammatory and chemokine genes. Addition of recombinant Shh to cultures of naive human CD4⁺ T cells in iTreg culture conditions increased FOXP3 expression. Our findings establish an important role for Shh upregulation in preventing AD, by increased Gli-driven, Treg cell–mediated immune suppression, paving the way for a potential new therapeutic strategy.

• Adaptive immunity
• Immunology
• Inflammation
• Skin
• T cells

• Cell signaling
• Developmental biology
• Embryoid bodies
• Embryonic stem cells

• Animals
• Cell Differentiation
• Cell Lineage/genetics
• Cell Movement
• Embryoid Bodies/cytology
• Embryoid Bodies/metabolism
• Extracellular Matrix/genetics
• Extracellular Matrix/metabolism
• Gene Editing/methods
• Gene Expression Regulation, Developmental
• Genes, Reporter
• Glypicans/deficiency
• Glypicans/genetics
• Green Fluorescent Proteins/genetics
• Green Fluorescent Proteins/metabolism
• Hedgehog Proteins/genetics
• Hedgehog Proteins/metabolism
• Luminescent Proteins/genetics
• Luminescent Proteins/metabolism
• Mice
• Mouse Embryonic Stem Cells/cytology
• Mouse Embryonic Stem Cells/metabolism
• N-Acetylglucosaminyltransferases/deficiency
• N-Acetylglucosaminyltransferases/genetics
• Neural Stem Cells/cytology
• Neural Stem Cells/metabolism
• Plasmids/chemistry
• Plasmids/metabolism
• Protein Transport
• Signal Transduction/genetics
• Transfection
• Red Fluorescent Protein

• R01 GM117090 NIGMS NIH HHS
• 1R01GM117090 National Institute of Health

The role of Hedgehog (Hh) signaling in vascular biology has first been highlighted in embryos by Pepicelli et al. in 1998 and Rowitch et al. in 1999. Since then, the proangiogenic role of the Hh ligands has been confirmed in adults, especially under pathologic conditions. More recently, the Hh signaling has been proposed to improve vascular integrity especially at the blood–brain barrier (BBB). However, molecular and cellular mechanisms underlying the role of the Hh signaling in vascular biology remain poorly understood and conflicting results have been reported. As a matter of fact, in several settings, it is currently not clear whether Hh ligands promote vessel integrity and quiescence or destabilize vessels to promote angiogenesis. The present review relates the current knowledge regarding the role of the Hh signaling in vasculature development, maturation and maintenance, discusses the underlying proposed mechanisms and highlights controversial data which may serve as a guideline for future research. Most importantly, fully understanding such mechanisms is critical for the development of safe and efficient therapies to target the Hh signaling in both cancer and cardiovascular/cerebrovascular diseases.

• Hedgehog
• angiogenesis
• blood–brain barrier
• endothelium
• vasculogenesis

The ventricular-subventricular zone (V-SVZ) of the forebrain is the source of neurogenic stem/precursor cells for adaptive and homeostatic needs throughout the life of most mammals. Here, we report that Suppressor of Fused (Sufu) plays a critical role in the establishment of the V-SVZ at early neonatal stages by controlling the proliferation of distinct subpopulations of stem/precursor cells. Conditional deletion of Sufu in radial glial progenitor cells (RGCs) at E13.5 resulted in a dramatic increase in the proliferation of Sox2+ Type B1 cells. In contrast, we found a significant decrease in Gsx2+ and a more dramatic decrease in Tbr2+ transit amplifying cells (TACs) indicating that innate differences between dorsal and ventral forebrain derived Type B1 cells influence Sufu function. However, many precursors accumulated in the dorsal V-SVZ or failed to survive, demonstrating that despite the over-proliferation of Type B1 cells, they are unable to transition into functional differentiated progenies. These defects were accompanied by reduced Gli3 expression and surprisingly, a significant downregulation of Sonic hedgehog (Shh) signaling. Therefore, these findings indicate a potential role of the Sufu-Gli3 regulatory axis in the neonatal dorsal V-SVZ independent of Shh signaling in the establishment and survival of functional stem/precursor cells in the postnatal dorsal V-SVZ.

Summary: Conditional deletion of Sufu causes dramatic expansion of neural stem/precursor cells in the neonatal ventricular-subventricular (SVZ) zone. This defect occurs through a Gli3-dependent mechanism resulting in the downregulation of Shh signaling.

• Gli3
• Neurogenesis
• Proliferation
• Sufu
• V-SVZ
• Ventricular-subventricular zone

• Dispatched
• Hedgehog
• Sonic Hedgehog
• cytonemes
• membrane trafficking
• morphogen

• Gli proteins
• Hedgehog signaling
• cancer
• developmental signaling
• morphogen signaling
• nuclear import
• posttranslational modifications
• primary cilia

• BBS9
• Gene expression signatures
• Innovative biotechnologies
• Mesenchymal stromal cells
• Nonsyndromic craniosynostosis
• Primary cilium

• Alternative Splicing/genetics
• Animals
• Cell Differentiation/genetics
• Cilia/metabolism
• Cranial Sutures/pathology
• Craniosynostoses/genetics
• Cytoskeletal Proteins
• Exons/genetics
• Female
• Gene Expression Profiling
• Gene Expression Regulation
• Gene Knockdown Techniques
• Hedgehog Proteins/metabolism
• Humans
• Infant
• Male
• Neoplasm Proteins/chemistry
• Neoplasm Proteins/genetics
• Osteogenesis/genetics
• Protein Isoforms/chemistry
• Protein Isoforms/genetics
• Protein Isoforms/metabolism
• Rats, Wistar
• Signal Transduction

• R01 DE016886 NIDCR NIH HHS

• Nonalcoholic fatty liver disease
• hedgehog
• treatment
• wound-healing response

Kif7 is a ciliary kinesin motor protein that regulates mammalian Hedgehog pathway activation through influencing structure of the primary cilium. Here we show that Kif7 is required for normal T-cell development, despite the fact that T-cells lack primary cilia. Analysis of Kif7-deficient thymus showed that Kif7-deficiency increases the early CD44+CD25+CD4-CD8- thymocyte progenitor population but reduces differentiation to CD4+CD8+ double positive (DP) cell. At the transition from DP to mature T-cell, Kif7-deficiency selectively delayed maturation to the CD8 lineage. Expression of CD5, which correlates with TCR signal strength, was reduced on DP and mature CD4 and CD8 cells, as a result of thymocyte-intrinsic Kif7-deficiency, and Kif7-deficient T-cells from radiation chimeras activated less efficiently when stimulated with anti-CD3 and anti-CD28 in vitro. Kif7-deficient thymocytes showed higher expression of the Hedgehog target gene Ptch1 than WT, but were less sensitive to treatment with recombinant Shh, and Kif7-deficient T-cell development was refractory to neutralisation of endogenous Hh proteins, indicating that Kif7-deficient thymocytes were unable to interpret changes in the Hedgehog signal. In addition, Kif7-deficiency reduced cell-surface MHCII expression on thymic epithelial cells.

• Immune response
• Immunity
• Immunology and Microbiology Section
• Kif7
• T-cell development
• sonic hedgehog
• thymic epithelial cell
• thymus

• Hedgehog pathway
• Liver disease
• Wound healing response

• Animals
• Cell Differentiation/genetics
• Cell Proliferation/genetics
• Cells, Cultured
• Down-Regulation/genetics
• Gene Expression Regulation
• Male
• Mice
• Mice, Knockout
• Nerve Tissue Proteins/physiology
• Receptors, G-Protein-Coupled/genetics
• Receptors, G-Protein-Coupled/metabolism
• Stem Cells/metabolism
• Stem Cells/physiology
• Taste Buds/cytology
• Taste Buds/metabolism
• Tongue/cytology
• Tongue/metabolism
• Zinc Finger Protein Gli3/physiology

• S10 OD018125 NIH HHS
• P30 DC011735 NIDCD NIH HHS
• R01 DC014286 NIDCD NIH HHS
• R01 DC014105 NIDCD NIH HHS
• R01 DC013807 NIDCD NIH HHS
• G20 OD020296 NIH HHS
• National Institutes of Health-National Institution on Deafness and Other Communication Disorders (NIH-NIDCD)
• National Institute on Deafness and Other Communication Disorders
• National Institutes of Health

• CD4
• Fetal thymus
• Gli3
• Mouse
• Positive selection
• Shh
• T-cell development
• Thymic epithelial cell (TEC)
• Thymocyte

All Hedgehog (Hh) proteins signal from producing cells to distant receiving cells despite being synthesized as N-and C-terminally lipidated, membrane-tethered molecules. To explain this paradoxical situation, over the past 15 years, several hypotheses have been postulated that tie directly into this property, such as Hh transport on cellular extensions called cytonemes or on secreted vesicles called lipophorins and exosomes. The alternative situation that tight membrane association merely serves to prevent unregulated Hh solubilization has been addressed by biochemical and structural studies suggesting Hh extraction from the membrane or proteolytic Hh release. While some of these models may act in different organisms, tissues or developmental programs, others may act together to specify Hh short- and long-range signaling in the same tissues. To test and rank these possibilities, we here review major models of Hh release and transport and hypothesize that the (bio)chemical and physical properties of firmly established, homologous, and functionally essential biochemical Hh modifications are adapted to specify and determine interdependent steps of Hh release, transport and signaling, while ruling out other steps. This is also described by the term “congruence”, meaning that the logical combination of biochemical Hh modifications can reveal their true functional implications. This combined approach reveals potential links between models of Hh release and transport that were previously regarded as unrelated, thereby expanding our view of how Hhs can steer development in a simple, yet extremely versatile, manner.