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FLASH GENE
Symbol SHH contributors: shn/ - updated : 18-12-2018
HGNC name sonic hedgehog
HGNC id 10848
Corresponding disease
DEL7Q36 chromosome 7q36 terminal deletion
HPE3 holoprosencephaly 3
MMDW Werner mesomelic syndrome
NSOC non-syndromic colobomatous microphthalmia
PPD2 preaxial polydactyly type II
TPT triphalangeal thumb-polysyndactyly syndrome
Location 7q36.3      Physical location : 155.595.557 - 155.604.967
Synonym name
  • sonic hedgehog (Drosophila) homolog
  • sonic hedgehog protein
    • Synonym symbol(s) HLP3, SMMCI, HHG1, TPTPS, MCOPCB5, ZRS
    DNA
    TYPE functioning gene
    STRUCTURE 9.41 kb     3 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence
    text structure a regulatory sequence ZRS driving spatiotemporal expression pattern in tetrapods, located 1Mb from SHH, into intron 5 of C7orf2 (LMBR1)
    MAPPING cloned Y linked N status confirmed
    Map cen - D7S1823 - D7S550 - SHH - D7S2465 - D7S2423 - qter
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    3 - 1576 19 462 - 2009 19784071
    EXPRESSION
    Type restricted
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveintestinelarge intestinecolon  
     liver    
    Nervousbraindiencephalonhypothalamus   Homo sapiens
    Skin/Tegumentskin appendageshairfollicle  
    Visualeye    
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Epithelialbarrier/lining   
    cells
    SystemCellPubmedSpeciesStageRna symbol
    NervousPurkinje cell
    cell lineage hematopoietic cell lines
    cell lines metastatic and localized prostate cancer cell lines
    fluid/secretion
    at STAGE
    physiological period embryo, fetal, neonatal, pregnancy
    Text
  • liver, lung, kidney, intestine, development of cortical and tectal plates, notochord and floor plate cells, gut endoderm, posterior limb buds, embryonic pancreatic beta cells
  • expressed throughout the ventral diencephalon and the oral ectoderm
    • PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • N terminal signaling domain (linking to PAL group)
  • secreted molecule undergoing an autoprocessing process driven by the C terminal domain, that produces a cholesterol-modified N terminal fragment responsible of all Hh signaling acticity
  • C terminal catalytic domain linking to cholesterol
    • conjugated GlycoP , LipoP
    HOMOLOGY
    interspecies ortholog to SHH, Pan troglodytes
    ortholog to Shh, Mus musculus
    ortholog to Shh, Rattus norvegicus
    intraspecies homolog to IHH
    Homologene
    FAMILY
  • hedgehog family
    • CATEGORY regulatory , signaling
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,Golgi
    basic FUNCTION
  • general ventralizing signal controling the size and step in midbrain pattern formation
  • inductive signal for somite differentiation and limb development at the anteroposterior axis, targeting BMP2 and HOXD genes through a FGF4 positive feedback loop
    • (regulating digit number and identity)
  • acting as an intramolecular cholesterol transferase, accounting for some of the effects of perturbed cholesterol biosynthesis
  • required for sclerotomal development cardiac morphogenesis, for gut development
  • required for the growth and differentiation of the oesophagus, trachea and lung
  • collaborating with NTN1 to guide commissural neuron axons to the midline
  • playing a dual role in promoting growth and metastasis of prostate cancer
  • may have a role in human tumorigenesis
  • hedgehog signaling, together with FGF8/10 signaling, synergizes to regulate expression of the LIM homeobox gene Lhx3, which has been proved to be essential for initial pituitary gland formation
  • requirement for Hedgehog signaling in sclerotomal development and a role in cardiac morphogenesis
  • functions in limb skeletal patterning to refining autopodial morphology, imposing pentadactyl constraint on the limb's polydactyl potential, and organizing digit identity specification
  • a regulator of adult hippocampal neural stem cells
  • plays a critical role in hair follicle development and skin cancer
  • essential for first pharyngeal arch development
  • involved in a negative feedback loop on HOXB8
  • playing a role in the regulation of erythroid proliferation and differentiation
  • promoting M
    • ller glia activation in the photoreceptor-damaged retina and enhancing neurogenic potential (may have therapeutic effects on M
    ller glia for promoting the regeneration of retinal neurons)
  • contributes to oligodendrocyte precursors proliferation and distribution along the optic nerve, in addition to their specification
  • dysregulation of the SHH pathway may be involved in the pathogenesis of diffuse large B-cell lymphoma
  • in limb development, SHH acts early, regulating patterning and growth
  • essential for establishing the anterior/posterior axis during regeneration by modulating wnt expression and may have a link with cilia function
  • stimulates prostate tumor growth by paracrine signaling and recapitulates embryonic gene expression in tumor myofibroblasts
  • Hh signalling is required to maintain both self-renewal and Nanog expression in cerebellar neural stem cells and HH regulates stem cell self-renewal through a p53-independent pathway
  • in addition to modulating VEGFA levels in stromal cells, SHH can directly affect angiogenesis via noncanonical signaling
  • suppresses a potential Fgf/Wnt signaling source in the forebrain
  • required for third ventricle formation and for production of an adequate telencephalic/diencephalic junction to separate the telencephalon and diencephalon
  • SHH and BMP7, which are expressed in the anterior and posterior hypothalamic ventral midline respectively, together repel hypothalamic axons towards the medial ventral midline
  • SHH acts as a major morphogen in patterning the limb buds
  • FGF8 and SHH promote the survival and maintenance of multipotent neural crest progenitors
  • SHH and IHH have been shown to control the induction of early cartilaginous differentiation
    • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS development
    text embryonic polarity, neuronal development
    PATHWAY
    metabolism
    signaling signal transduction
    a component
    INTERACTION
    DNA
    RNA
    small molecule other,
  • cholesterol
    • protein
  • multitransmembrane protein Patched, PTCH
  • rowth-arrest specific gene 1, Gas1
  • Shh is a downstream target of Fgf10/Fgfr2b signaling
  • WNT7B during mammalian tooth development
  • GLI3(counteract GLI3-mediated repression of key regulator genes, cell survival and progression of limb bud development)
  • GLI gene in mediating the carcinogenic effect of hedgehog pathway activation
  • SMO (essential component of the HH signaling)
  • regulating CRH signal transduction in the adult pituitary
  • SCUBE2
  • inducing ARRB1 accumulation and localization to the nucleus, where it participates in enhancing expression of CDKN1B, whose accumulation eventually drives granule neuron precursors (CGNPs) cell cycle exit
  • TWIST2 regulates early limb morphogenesis through a role in terminating the SHH/GREM1/FGF autoregulatory loop
  • connection between SHH-GLI1 signaling and S100A4 regulation, which imply that S100A4 might be one of the key factors in EMT mediated by SHH-GLI1 signaling in pancreatic cancer (pMID: 25072505)
  • TGIF1 and TGIF2 regulate the TGFB1/NODAL signaling pathway and sonic hedgehog (SHH) signaling independently
    • cell & other
    REGULATION
    activated by GLI family zinc finger 2, GLI2
    Other cholesterol is required for the long-range activity of SHH during limb-patterning
    negatively regulated by GLI3
    ASSOCIATED DISORDERS
    corresponding disease(s) HPE3 , NSOC , DEL7Q36 , TPT , PPD2 , MMDW
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --other  
    abnormal expression in the floor plate of embryos with craniorachischisis and spinabifida
    tumoral       gain of function
    activated in sporadic basal cell carcinomas and medulloblastomas
    tumoral     --over  
    overexpressed in pancreatic cancer and in distal trisomy 7q
    Susceptibility
  • to combined pituitary hormone deficiency
  • to orofacial cleft
    • Variant & Polymorphism SNP
  • SNP in two Hedgehog genes, SHH and HHIP, are genetic cause of combined pituitary hormone deficiency
  • variants in SHH, RORA, MRPL53, ACVR1, and GDF11 may contribute to risk of orofacial clefts
    • Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • disruption of mouse Sonic hedgehog gene leads to early defects: establishment or maintenance of midline structures, such as the notochord and the floorplate, and later defects: absence of distal limb structures, cyclopia, ventral cell types within the neural tube, spinal column and most of the ribs
  • transgenic mice overexpressing SHH in the skin develop many features of basal cell nevus syndrome
  • mice with a targeted deletion of Sonic hedgehog have foregut defects and homozygous Shh-null mutant mice show oesophageal atresia/stenosis, tracheo-oesophageal fistula and tracheal and lung anomalies
  • Sonic hedgehog mutant mice display intestinal transformation of the stomach, duodenal stenosis (obstruction), abnormal innervation of the gut and imperforate anus. Indian hedgehog mutant mice show reduced epithelial stem cell proliferation and differentiation, together with features typical of Hirschsprung's disease
  • administration of ethanol to chick embryos results in a dramatic loss of Shh and a loss of transcripts involved in Shh signaling pathways exhibit a highly characteristic pattern of cell death. Embryos display dying cells in the premigratory and migratory neural crest cells that normally populate most facial structures
  • Shh(-/-) mice exhibit an arrest in hair follicle development with reduced cell proliferation
  • pancreata of Pdx-Shh mice, in which Shh is misexpressed in the pancreatic endoderm, develop abnormal tubular structures, a phenocopy of human PanIN-1 and -2
  • hh gene expression at the embryonic midline controls eye degeneration in blind cavefish
  • functional interaction between beta-arrestin 2 and Smoothened may be critical to regulate Hh signaling in zebrafish development
  • homozygous Short digits (Dsh) mutant mice display dysregulation of Shh expression causing local upregulation of hedgehog target genes; Gli1-3, patched, and Pthlh, and the downregulation of Ihh and Gdf5, which results in shortening of the digits through an arrest of chondrocyte differentiation and the disruption of joint development
  • Shh mutant embryos display a hypoplastic first pharyngeal arch and the growth of the maxillary arch and proximal mandibular arch is severely defective
  • in the Shh(-/-) thymus the ratio of CD4/CD8 cells and both positive and negative selection of a transgenic TCR were increased
  • elevated ectopic Shh signaling in mice can impair dorsal telencephalic midline morphogenesis and lead to non-cleavage of midline structures
  • the third ventricle is blocked in mice Shh null mutants similar to human holoprosencephaly
  • a malformed telencephalic/diencephalic junction in the mouse Shh mutant forebrain