Sonic Hedgehog (SHH)

Sonic HedgeHog, also known as sonic hedgehog protein, belongs to the hedgehog family. It cannot be detected in adult tissues while can be found in fetal intestine, liver, lung, and kidney. Sonic HedgeHog is a protein that is vital in guding the early embryo. It has been associated as the major inductive signal in patterning of the ventral neural tube, the anterior-posterior limb axis, and the ventral somites. Sonic HedgeHog intercellular signal is essential for a various patterning events during development: signal produced by the notochord that induces ventral cell fate in the neural tube and somites, and the polarizing signal for patterning of the anterior-posterior axis of the developing limb bud. Sonic HedgeHog binds to the patched receptor, which functions in association with smoothened, to activate the transcription of target genes. In the absence of sonic HedgeHog, patched receptor represses the constitutive signaling activity of smoothened. Sonic HedgeHog also regulates another factor, the gli oncogene. Defects in sonic hedgehog can cause microphthalmia isolated with coloboma type 5, triphalangeal thumb-polysyndactyly syndrome and holoprosencephaly type 3.

Sonic Hedgehog (SHH) Related Areas

Signal Transduction>>Transcription Factor & Regulator>>SHH / Sonic hedgehog

Sonic Hedgehog (SHH) Alternative Names

HHG1, HLP3, HPE3, MCOPCB5, SMMCI, TPT, TPTPS, sonic hedgehog homolog, sonic hedgehog protein [Homo sapiens]

9530036O11Rik, Dsh, Hhg1, Hx, Hxl3, M100081, HHG-1, hemimelic extra toes, short digits, sonic hedgehog protein [Mus musculus]

Summaries for Sonic Hedgehog (SHH)

Entrez Gene summary for Sonic Hedgehog (SHH):

SHH gene encodes a protein that is instrumental in patterning the early embryo. It has been implicated as the key inductive signal in patterning of the ventral neural tube, the anterior-posterior limb axis, and the ventral somites. Of three human proteins showing sequence and functional similarity to the sonic hedgehog protein of Drosophila, this protein is the most similar. The protein is made as a precursor that is autocatalytically cleaved; the N-terminal portion is soluble and contains the signalling activity while the C-terminal portion is involved in precursor processing. More importantly, the C-terminal product covalently attaches a cholesterol moiety to the N-terminal product, restricting the N-terminal product to the cell surface and preventing it from freely diffusing throughout the developing embryo. Defects in this protein or in its signalling pathway are a cause of holoprosencephaly (HPE), a disorder in which the developing forebrain fails to correctly separate into right and left hemispheres. HPE is manifested by facial deformities. It is also thought that mutations in this gene or in its signalling pathway may be responsible for VACTERL syndrome, which is characterized by vertebral defects, anal atresia, tracheoesophageal fistula with esophageal atresia, radial and renal dysplasia, cardiac anomalies, and limb abnormalities. Additionally, mutations in a long range enhancer located approximately 1 megabase upstream of SHH gene disrupt limb patterning and can result in preaxial polydactyly. [provided by RefSeq, Jul 2008]

OMIM - description for Sonic Hedgehog (SHH):

The SHH gene encodes sonic hedgehog, a secreted protein that is involved in establishing cell fates at several points during development. SHH belongs to a family of vertebrate genes related to the Drosophila gene 'hedgehog' (hh) that encodes inductive signals during embryogenesis (Echelard et al., 1993; Roelink et al., 1994). These genes are involved in the organization and morphology of the developing embryo, which is established through a series of inductive interactions (Marigo et al., 1995).
Riddle et al. (1993) named the chicken homolog of the Drosophila gene 'Sonic hedgehog' after the Sega computer game cartoon character. Mammalian homologs of hh include Sonic hedgehog (Shh), Indian hedgehog (Ihh; ), and desert hedgehog (Dhh; ) (Echelard et al., 1993).

Wikipedia summary for Sonic Hedgehog (SHH):

Sonic hedgehog homolog (SHH) is one of three proteins in the mammalian signaling pathway family called hedgehog, the others being desert hedgehog (DHH) and Indian hedgehog (IHH). SHH is the best studied ligand of the hedgehog signaling pathway. It plays a key role in regulating vertebrate organogenesis, such as in the growth of digits on limbs and organization of the brain. Sonic hedgehog is the best established example of a morphogen as defined by Lewis Wolpert's French flag model—a molecule that diffuses to form a concentration gradient and has different effects on the cells of the developing embryo depending on its concentration. SHH remains important in the adult. It controls cell division of adult stem cells and has been implicated in development of some cancers.

Human Sonic Hedgehog (SHH) Protein General Information

 

• Protein names: Sonic hedgehog protein
  Short name=SHH
• Sequence length: 462 AA.
• Domain: Signal
• Sequence similarities: Belongs to the hedgehog family.
• Post-translational modification: The C-terminal domain displays an autoproteolysis activity and a cholesterol transferase activity. Both activities result in the cleavage of the full-length protein and covalent attachment of a cholesterol moiety to the C-terminal of the newly generated N-terminal fragment (N-product). The N-product is the active species in both local and long-range signaling, whereas the C-product has no signaling activity. Cholesterylation is required for N-product targeting to lipid rafts and multimerization By similarity. N-palmitoylation of Cys-24 by HHAT is required for N-product multimerization and full activity By similarity.
• Subunit structure: Interacts with HHATL/GUP1 which negatively regulates HHAT-mediated palmitoylation of the SHH N-terminus. N-product is active as a multimer
• Subcellular location: Sonic hedgehog protein C-product: Secreted › extracellular space By similarity. Note: The C-terminal peptide diffuses from the cell .
  Sonic hedgehog protein N-product: Cell membrane; Lipid-anchor . Note: The N-product either remains associated with lipid rafts at the cell surface, or forms freely diffusible active multimers with its hydrophobic lipid-modified N- and C-termini buried inside .
• Tissue specificity: Expressed in fetal intestine, liver, lung, and kidney. Not expressed in adult tissues.
• Mass spectrometry: Molecular mass is 19.560 Da from positions 24 - 197. Determined by ESI. Soluble N-product, purified from insect cells.
  Molecular mass is 20.167 Da from positions 24 - 197. Determined by ESI. Membrane-bound N-product, purified from insect cells.
• Involvement in disease: Defects in SHH are the cause of microphthalmia isolated with coloboma type 5 (MCOPCB5) . Microphthalmia is a clinically heterogeneous disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues. Ocular abnormalities like opacities of the cornea and lens, scaring of the retina and choroid, cataract and other abnormalities like cataract may also be present. Ocular colobomas are a set of malformations resulting from abnormal morphogenesis of the optic cup and stalk, and the fusion of the fetal fissure (optic fissure).
  Defects in SHH are the cause of holoprosencephaly type 3 (HPE3) . Holoprosencephaly (HPE) [MIM:236100] is the most common structural anomaly of the brain, in which the developing forebrain fails to correctly separate into right and left hemispheres. Holoprosencephaly is genetically heterogeneous and associated with several distinct facies and phenotypic variability. The majority of HPE3 cases are apparently sporadic, although clear examples of autosomal dominant inheritance have been described. Interestingly, up to 30% of obligate carriers of HPE3 gene in autosomal dominant pedigrees are clinically unaffected.
  Defects in SHH are a cause of solitary median maxillary central incisor (SMMCI) . SMMCI is a rare dental anomaly characterized by the congenital absence of one maxillary central incisor.
  Defects in SHH are the cause of triphalangeal thumb-polysyndactyly syndrome (TPTPS) . TPTPS is an autosomal dominant syndrome characterized by a wide spectrum of pre- and post-axial abnormalities due to altered SHH expression pattern during limb development. TPTPS mutations have been mapped to the 7q36 locus in the LMBR1 gene which contains in its intron 5 a long-range cis-regulatory element of SHH expression.

General information above from UniProt

Function for Sonic Hedgehog (SHH) Protein

UniProtKB:

Sonic hedgehog binds to the patched (PTC) receptor, which functions in association with smoothened (SMO), to activate the transcription of target genes. In the absence of SHH, PTC represses the constitutive signaling activity of SMO. Sonic hedgehog also regulates another target, the gli oncogene. Sonic hedgehog is intercellular signal essential for a variety of patterning events during development: signal produced by the notochord that induces ventral cell fate in the neural tube and somites, and the polarizing signal for patterning of the anterior-posterior axis of the developing limb bud. Sonic hedgehog displays both floor plate- and motor neuron-inducing activity. The threshold concentration of N-product required for motor neuron induction is 5-fold lower than that required for floor plate induction.

Genatlas:

• Sonic hedgehog is general ventralizing signal controling the size and step in midbrain pattern formation
• Sonic hedgehog is 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)
• Sonic hedgehog acts as an intramolecular cholesterol transferase, accounting for some of the effects of perturbed cholesterol biosynthesis
• Sonic hedgehog is required for sclerotomal development cardiac morphogenesis, for gut development
• Sonic hedgehog is required for the growth and differentiation of the oesophagus, trachea and lung
• Sonic hedgehog collaborates with NTN1 to guide commissural neuron axons to the midline
• Sonic hedgehog plays a dual role in promoting growth and metastasis of prostate cancer
• Sonic hedgehog may have a role in human tumorigenesis
• Sonic hedgehog is 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
• Sonic hedgehog is requirement for Hedgehog signaling in sclerotomal development and a role in cardiac morphogenesis
• Sonic hedgehog functions in limb skeletal patterning to refining autopodial morphology, imposing pentadactyl constraint on the limb's polydactyl potential, and organizing digit identity specification
• Sonic hedgehog is a regulator of adult hippocampal neural stem cells
• Sonic hedgehog plays a critical role in hair follicle development and skin cancer
• Sonic hedgehog is essential for first pharyngeal arch development
• Sonic hedgehog is involved in a negative feedback loop on HOXB8
• Sonic hedgehog plays a role in the regulation of erythroid proliferation and differentiation
• Sonic hedgehog promotes Müller glia activation in the photoreceptor-damaged retina and enhances neurogenic potential (may have therapeutic effects on Müller glia for promoting the regeneration of retinal neurons)
• Sonic hedgehog 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
• Sonic hedgehog is essential for establishing the anterior/posterior axis during regeneration by modulating wnt expression and may have a link with cilia function
• Sonic hedgehog 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

Homology for human Sonic Hedgehog (SHH)

• ortholog to SHH, Pan troglodytes
• ortholog to Shh, Mus musculus
• ortholog to Shh, Rattus norvegicus
• homolog to IHH

Phenotype Information for Sonic Hedgehog (SHH)

• Gene/Locus: SHH, HPE3, HLP3, SMMCI, MCOPCB5
• Phenotype: Holoprosencephaly-3
  Microphthalmia with coloboma 5
  Schizencephaly
  Single median maxillary central incisor

Phenotype Information for Sonic Hedgehog (SHH) from OMIM (Online Mendelian Inheritance in Man)