SHH (Sonic hedgehog)

2002-02-01   Thierry Magnaldo 

CNRS, UPR 2169, Instabilit@eacute; Génétique et Cancer, Institut André LWOFF, 7, rue Guy Moquet, 94801 Villejuif, France





3 exons, all 3 coding, cDNA to mRNA is 1576 bp


coding sequence : nucleotides 152 to 1540. Two transcription start sites have been described.



SHH is a secreted protein synthesised as a precursor molecule of 462 amino acids (45kDa); it harbors a signal sequence of 23 amino acids. Following removal of the signal sequence, a cholestreol-mediated autocatalystic cleavage results in a NH2 and a COOH subportions (N-SHH and C-SHH, respectively 19kDa and 25 kDa). N-SHH emcompasses amino acids 24-196. C-SHH encompasses amino acids 197-463. The C-SHH moeity bears the cholesterol transferase activity. Upon processing, the cholestreol molecule is covalently transfered to the C terminus of N-SHH through a nucleophilic substitution. Post-translational processing of N-SHH is thought to be necessary to its correct spatial distribution and effects during embryonic patterning. Except its role in the autocatalytic cleavage of precursor SHH, no biological activity of C-SHH has been evidenced.


SHH is the most broadly expressed member the hedgehog family. It is involved in the development of axial skeleton, notochord, spinal cord, floor plate, gut endoderm, and posterior limb (see also: Skeletal development in human: a model for the study of developmental genes .Ihh and Dhh play distinctive roles in the development of cartilage, and male germ cells respectively. In the adult, SHH plays roles in the hair follicle growth and cycle.


SHH is secreted from producing cells to reach the surface of target cells were it interacts with its receptor, the multipass transmembrane protein PATCHED.


SHH is implicated in segment polarisation. SHH biochemical function is the binding of PATCHED. This interaction modulates the activity of a third transmembrane protein called Smothened (SMO) apparented with G proteins-coupled receptors. SHH binding results in activation of the SHH/PATCHED pathway which eventually results in the modulation of the balance between cell proliferation and differentiation. In the absence of SHH, PATCHED acts as a constitutive repressor of the activity of SMO by posttranscriptionnal modifications. In contrast, the presence of SHH releaves PATCHED-mediated SMO inhibition and results in cell proliferation and transriptional activation of SHH target genes (PATCHED, Wingless, DPP, in Drosophila ; PATCHED, Wnt, BMPs, in vertebrates) involving Ci (Drosophila) or Gli (Gli-1, 2, 3, vertebrates) transcriptional factors. Most notably, SHH-induced SMO activation proceeds with transcription of PATCHED itself, suggesting a retroregulation loop, and hence a narrow maintenance of both free SHH and PATCHED/SMO complex concentration at the cell surface.
The important role of the SHH/PATCHED pathway in development and tissue homeostasis is attested by genetic disorders linked to specific dysregulation of this pathway. Familial mutations of PATCHED are linked to the Gorlins or Nevoid Basal cell carcinoma syndrome. SHH mutations may result in sporadic or familial Holoproencepaly HPE (see below).


Alignement of full length human SHH and human IHH cDNAs reveals 71.608 % identities (GCG, Bestfit).



To the contrary of PATCHED, which mutation may result in familial predisposition to basal cell carcinoma and meduloblastoma, SHH mutations only result in developmental abnormalities. To date, there is actually no clear evidence that SHH mutation may be " naturally " associated with cancer. However, transgenic mice overexpressing SHH in the epidermal layer of skin develop basal cell carcinoma-like tumors.
Most SHH mutations that have been identified are associated with sporadic or familial cases of holoproencephaly (HPE, 1/133000 to 1/16000 viable birth) and Solitary Median Maxillary Central Incisor (SMMCI). Mutations are sparse over the SHH coding region. All types of mutation have been described. No evident correlation between mutation types and location, and patient phenotypes can be drawn

Implicated in


Pubmed IDLast YearTitleAuthors
105747601999Inhibition of sonic hedgehog signaling in vivo results in craniofacial neural crest cell death.Ahlgren SC et al
105459951999Ultraviolet and ionizing radiation enhance the growth of BCCs and trichoblastomas in patched heterozygous knockout mice.Aszterbaum M et al
112571092001The hedgehog pathway and basal cell carcinomas.Bale AE et al
113315872001Patched1 interacts with cyclin B1 to regulate cell cycle progression.Barnes EA et al
107169162000EMBO Gold Medal 1999. Waiting periods, instructive signals and positional information.Basler K et al
88965711996Identification of Sonic hedgehog as a candidate gene responsible for holoprosencephaly.Belloni E et al
102204281999High levels of patched gene mutations in basal-cell carcinomas from patients with xeroderma pigmentosum.Bodak N et al
117888372002A critical role for sonic hedgehog signaling in the early expansion of the developing brain.Britto J et al
115323962001Monstrous attempts at adnexogenesis: regulating hair follicle progenitors through Sonic hedgehog signaling.Callahan CA et al
94733231998Control of dorsoventral somite patterning by Wnt-1 and beta-catenin.Capdevila J et al
88982071996Dual roles for patched in sequestering and transducing Hedgehog.Chen Y et al
88377701996Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function.Chiang C et al
109804292000On the range of hedgehog signaling.Chuang PT et al
100508551999Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein.Chuang PT et al
117182632001A mouse model for medulloblastoma and basal cell nevus syndrome.Corcoran RB et al
93498221997Activation of the transcription factor Gli1 and the Sonic hedgehog signalling pathway in skin tumours.Dahmane N et al
117481552001The Sonic Hedgehog-Gli pathway regulates dorsal brain growth and tumorigenesis.Dahmane N et al
100757171999Sonic Hedgehog-induced activation of the Gli1 promoter is mediated by GLI3.Dai P et al
108381432000UV-specific mutations of the human patched gene in basal cell carcinomas from normal individuals and xeroderma pigmentosum patients.Daya-Grosjean L et al
109661132000Hedgehog induces opposite changes in turnover and subcellular localization of patched and smoothened.Denef N et al
115334912001Regulation of Wnt signaling and embryo patterning by an extracellular sulfatase.Dhoot GK et al
96360691998Diminished Sonic hedgehog signaling and lack of floor plate differentiation in Gli2 mutant mice.Ding Q et al
86581351996Sending and receiving the hedgehog signal: control by the Drosophila Gli protein Cubitus interruptus.Domínguez M et al
89295351996Two critical periods of Sonic Hedgehog signaling required for the specification of motor neuron identity.Ericson J et al
105088561999Sonic hedgehog opposes epithelial cell cycle arrest.Fan H et al
92121091997Induction of basal cell carcinoma features in transgenic human skin expressing Sonic Hedgehog.Fan H et al
75795231994The hedgehog gene family in Drosophila and vertebrate development.Fietz MJ et al
105001131999Sonic hedgehog protein signals not as a hydrolytic enzyme but as an apparent ligand for patched.Fuse N et al
114553892001Mutations in IHH, encoding Indian hedgehog, cause brachydactyly type A-1.Gao B et al
103957911999Overexpression of ptc1 inhibits induction of Shh target genes and prevents normal patterning in the neural tube.Goodrich LV et al
86813791996Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome.Hahn H et al
95852391998Rhabdomyosarcomas and radiation hypersensitivity in a mouse model of Gorlin syndrome.Hahn H et al
100966021999Expression of sonic hedgehog, patched, and Gli1 in developing taste papillae of the mouse.Hall JM et al
111301772000The role of cholesterol in Shh signaling and teratogen-induced holoprosencephaly.Incardona JP et al
95296111998The patched gene in development and cancer.Ingham PW et al
79503211994Mechanisms of limb patterning.Johnson RL et al
110816242000Transducing the hedgehog signal.Kalderon D et al
98788251998Promoter structure of human sonic hedgehog gene.Kitazawa S et al
99898361999A frequent activated smoothened mutation in sporadic basal cell carcinomas.Lam CW et al
80011461994Sonic hedgehog and Fgf-4 act through a signaling cascade and feedback loop to integrate growth and patterning of the developing limb bud.Laufer E et al
115729862001Evidence that the WNT-inducible growth arrest-specific gene 1 encodes an antagonist of sonic hedgehog signaling in the somite.Lee CS et al
79850231994Autoproteolysis in hedgehog protein biogenesis.Lee JJ et al
76713081995A molecular pathway determining left-right asymmetry in chick embryogenesis.Levin M et al
97315321998Sonic hedgehog is essential to foregut development.Litingtung Y et al
101022701999Hedgehog controls limb development by regulating the activities of distinct transcriptional activator and repressor forms of Cubitus interruptus.Méthot N et al
118013252002Hedgehog patterns midbrain ARChitecture.Machold R et al
105253341999In vivo regulation of somite differentiation and proliferation by Sonic Hedgehog.Marcelle C et al
89067941996Biochemical evidence that patched is the Hedgehog receptor.Marigo V et al
89485901996Sonic hedgehog differentially regulates expression of GLI and GLI3 during limb development.Marigo V et al
89713391996Sonic hedgehog regulates patterning in early embryos.Marigo V et al
87903321996Regulation of patched by sonic hedgehog in the developing neural tube.Marigo V et al
118145612002Sonic hedgehog in CNS development: one signal, multiple outputs.Martí E et al
106600402000More surprises in the Hedgehog signaling pathway.McMahon AP et al
97554531998Human developmental disorders and the Sonic hedgehog pathway.Ming JE et al
97335691998Stage-specific effects of sonic hedgehog expression in the epidermis.Morgan BA et al
94627341998Ptch2, a second mouse Patched gene is co-expressed with Sonic hedgehog.Motoyama J et al
94747421998Hematopoietic deficiencies in c-mpl and TPO knockout mice.Murone M et al
107102302000Holoprosencephaly: molecular study of a California population.Nanni L et al
114711642001SHH mutation is associated with solitary median maxillary central incisor: a study of 13 patients and review of the literature.Nanni L et al
117824042002Expression of DeltaNLef1 in mouse epidermis results in differentiation of hair follicles into squamous epidermal cysts and formation of skin tumours.Niemann C et al
107253632000Induction of basal cell carcinomas and trichoepitheliomas in mice overexpressing GLI-1.Nilsson M et al
104413311999Expression of the Sonic hedgehog (SHH ) gene during early human development and phenotypic expression of new mutations causing holoprosencephaly.Odent S et al
86258051996Evidence that Shh cooperates with a retinoic acid inducible co-factor to establish ZPA-like activity.Ogura T et al
91152101997Basal cell carcinomas in mice overexpressing sonic hedgehog.Oro AE et al
118075562002Prediction of central nervous system embryonal tumour outcome based on gene expression.Pomeroy SL et al
109839932000Hedgehog signal transduction in the posterior compartment of the Drosophila wing imaginal disc.Ramírez-Weber FA et al
115206642001Characterization of Wnt gene expression in developing and postnatal hair follicles and identification of Wnt5a as a target of Sonic hedgehog in hair follicle morphogenesis.Reddy S et al
82695181993Sonic hedgehog mediates the polarizing activity of the ZPA.Riddle RD et al
75880511995Sonic hedgehog is an endodermal signal inducing Bmp-4 and Hox genes during induction and regionalization of the chick hindgut.Roberts DJ et al
115989562001Midline and laterality defects: left and right meet in the middle.Roessler E et al
115533302001Hedgehog signaling pathway is essential for pancreas specification in the zebrafish embryo.Roy S et al
103755101999Gli proteins encode context-dependent positive and negative functions: implications for development and disease.Ruiz i Altaba A et al
115260812001Local retinoid signaling coordinates forebrain and facial morphogenesis by maintaining FGF8 and SHH.Schneider RA et al
111527632001Controls of hair follicle cycling.Stenn KS et al
89067871996The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog.Stone DM et al
112846922001Enhanced potency of human Sonic hedgehog by hydrophobic modification.Taylor FR et al
115929782001Sonic hedgehog restricts adhesion and migration of neural crest cells independently of the Patched- Smoothened-Gli signaling pathway.Testaz S et al
91928031997Human patched (PTCH) mRNA is overexpressed consistently in tumor cells of both familial and sporadic basal cell carcinoma.Undén AB et al
88409601996Mutations in the human homologue of Drosophila patched (PTCH) in basal cell carcinomas and the Gorlin syndrome: different in vivo mechanisms of PTCH inactivation.Unden AB et al
91222071997Hedgehog signaling regulates transcription through cubitus interruptus, a sequence-specific DNA binding protein.Von Ohlen T et al
93544201997Trichoepitheliomas contain somatic mutations in the overexpressed PTCH gene: support for a gatekeeper mechanism in skin tumorigenesis.Vorechovský I et al
107714692000Regular articles: conditional disruption of hedgehog signaling pathway defines its critical role in hair development and regeneration.Wang LC et al
112833162001The developmental biology of brain tumors.Wechsler-Reya R et al
106306371999The hedgehog signalling pathway in tumorigenesis and development.Wicking C et al
94225111998Activating Smoothened mutations in sporadic basal-cell carcinoma.Xie J et al
100290631999PTCH2, a novel human patched gene, undergoing alternative splicing and up-regulated in basal cell carcinomas.Zaphiropoulos PG et al
105253541999Sonic hedgehog and BMP2 exert opposing actions on proliferation and differentiation of embryonic neural progenitor cells.Zhu G et al

Other Information

Locus ID:

NCBI: 6469
MIM: 600725
HGNC: 10848
Ensembl: ENSG00000164690


dbSNP: 6469
ClinVar: 6469
TCGA: ENSG00000164690


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Hedgehog signaling pathwayKEGGko04340
Axon guidanceKEGGko04360
Basal cell carcinomaKEGGko05217
Hedgehog signaling pathwayKEGGhsa04340
Axon guidanceKEGGhsa04360
Pathways in cancerKEGGhsa05200
Basal cell carcinomaKEGGhsa05217
Proteoglycans in cancerKEGGhsa05205
Proteoglycans in cancerKEGGko05205
Hedgehog signalingKEGGhsa_M00678
Hedgehog signalingKEGGM00678
Diseases of signal transductionREACTOMER-HSA-5663202
Hh mutants abrogate ligand secretionREACTOMER-HSA-5387390
Hh mutants that don't undergo autocatalytic processing are degraded by ERADREACTOMER-HSA-5362768
Signal TransductionREACTOMER-HSA-162582
Signaling by GPCRREACTOMER-HSA-372790
GPCR ligand bindingREACTOMER-HSA-500792
Class B/2 (Secretin family receptors)REACTOMER-HSA-373080
Signaling by HedgehogREACTOMER-HSA-5358351
Hedgehog ligand biogenesisREACTOMER-HSA-5358346
Release of Hh-Np from the secreting cellREACTOMER-HSA-5362798
Hedgehog 'on' stateREACTOMER-HSA-5632684
Ligand-receptor interactionsREACTOMER-HSA-5632681
Activation of SMOREACTOMER-HSA-5635838
HHAT G278V abrogates palmitoylation of Hh-NpREACTOMER-HSA-5658034


Pubmed IDYearTitleCitations
145204132003Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis.462
145204112003Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours.370
128376952003A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly.359
126295532003Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer.302
186915472008Acquisition of granule neuron precursor identity is a critical determinant of progenitor cell competence to form Shh-induced medulloblastoma.252
176280162007Cyclopamine-mediated hedgehog pathway inhibition depletes stem-like cancer cells in glioblastoma.222
173924272007Melanomas require HEDGEHOG-GLI signaling regulated by interactions between GLI1 and the RAS-MEK/AKT pathways.213
221444662011The Hedgehog pathway promotes blood-brain barrier integrity and CNS immune quiescence.202
188294782008Sonic hedgehog promotes desmoplasia in pancreatic cancer.185
153142192004Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling.172


Thierry Magnaldo

SHH (Sonic hedgehog)

Atlas Genet Cytogenet Oncol Haematol. 2002-02-01

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