SHH (Sonic hedgehog)

Identity

HGNC	SHH
Location	7q36
Local_order	Markers: RH69762, StSG39143

Note	Sonic hedgehog (SHH) is the vertebrate orthologue of Hedeghog (Hh) a morphogen signalling molecule discovered in a mutant drosophila (fruit fly). In addition to SHH, two other distinct Hh homologues have been cloned in vertebrates, Indian Hedgehog (Ihh) and (Dhh).

DNA/RNA

Description	3 exons, all 3 coding, cDNA to mRNA is 1576 bp
Transcription	coding sequence : nucleotides 152 to 1540. Two transcription start sites have been described.

Protein

Description	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.
Expression	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.
Localisation	SHH is secreted from producing cells to reach the surface of target cells were it interacts with its receptor, the multipass transmembrane protein PATCHED.
Function	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 Gorlin's or Nevoid Basal cell carcinoma syndrome. SHH mutations may result in sporadic or familial Holoproencepaly HPE (see below).
Homology	Alignement of full length human SHH and human IHH cDNAs reveals 71.608 % identities (GCG, Bestfit).

Mutations

Germinal

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

External links

	Nomenclature
HGNC	SHH   10848
Entrez_Gene	SHH  6469  sonic hedgehog homolog (Drosophila)
	Cards
Atlas	SHHID378
GeneCards	SHH
Ensembl	SHH [Search_View]   ENSG00000164690 [Gene_View]
Genatlas	SHH
GeneLynx	SHH
eGenome	SHH
euGene	6469
	Genomic and cartography
GoldenPath	SHH  -  7q36   chr7:155288319-155297728 -  7q36   [Description]    (hg18-Mar_2006)
Ensembl	SHH - 7q36 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	SHH
	Gene and transcription
Genbank	AY927450 [ ENTREZ ]
Genbank	BC111925 [ ENTREZ ]
Genbank	L38518 [ ENTREZ ]
RefSeq	NM_000193 [ SRS ]    NM_000193 [ ENTREZ ]
RefSeq	AC_000050 [ SRS ]    AC_000050 [ ENTREZ ]
RefSeq	AC_000068 [ SRS ]    AC_000068 [ ENTREZ ]
RefSeq	AC_000139 [ SRS ]    AC_000139 [ ENTREZ ]
RefSeq	NC_000007 [ SRS ]    NC_000007 [ ENTREZ ]
RefSeq	NG_007504 [ SRS ]    NG_007504 [ ENTREZ ]
RefSeq	NT_007741 [ SRS ]    NT_007741 [ ENTREZ ]
RefSeq	NT_079596 [ SRS ]    NT_079596 [ ENTREZ ]
RefSeq	NW_001839100 [ SRS ]    NW_001839100 [ ENTREZ ]
RefSeq	NW_923796 [ SRS ]    NW_923796 [ ENTREZ ]
AceView	SHH AceView - NCBI
Unigene	Hs.164537 [ SRS ]    Hs.164537 [ NCBI ]     HS164537 [ spliceNest ]
Fast-db	13351 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	Q15465 [ SRS]    Q15465 [ EXPASY ]     Q15465 [ INTERPRO ]     Q15465 [ UNIPROT ]
Prosite	PS50817 INTEIN_N_TER [ SRS ]    PS50817 INTEIN_N_TER [ Expasy ]
Interpro	IPR003586 Hedgehog_hint_C [ SRS ]    IPR003586 Hedgehog_hint_C [ EBI ]
Interpro	IPR003587 Hedgehog_hint_N [ SRS ]    IPR003587 Hedgehog_hint_N [ EBI ]
Interpro	IPR000320 HH_signal [ SRS ]    IPR000320 HH_signal [ EBI ]
Interpro	IPR006141 Intein_splicing_site [ SRS ]    IPR006141 Intein_splicing_site [ EBI ]
Interpro	IPR001657 Peptidase_C46 [ SRS ]    IPR001657 Peptidase_C46 [ EBI ]
Interpro	IPR001767 Peptidase_C46_hint [ SRS ]    IPR001767 Peptidase_C46_hint [ EBI ]
CluSTr	Q15465
Pfam	PF01085 HH_signal [ SRS ]    PF01085 HH_signal [ Sanger ]    pfam01085 [ NCBI-CDD ]
Pfam	PF01079 Hint [ SRS ]    PF01079 Hint [ Sanger ]    pfam01079 [ NCBI-CDD ]
Smart	SM00305 HintC [EMBL]
Smart	SM00306 HintN [EMBL]
Blocks	Q15465
HPRD	02838
	Protein Interaction databases
DIP	Q15465
IntAct	Q15465
	Polymorphism : SNP, mutations, diseases
OMIM	120200;142945;147250;174500;600725;611638    [ map ]
GENECLINICS	120200;142945;147250;174500;600725;611638
SNP	SHH [dbSNP-NCBI]
SNP	NM_000193 [SNP-NCI]
SNP	SHH [GeneSNPs - Utah]  SHH] [HGBASE - SRS]
HAPMAP	SHH [HAPMAP]
HGMD	SHH
	General knowledge
Family Browser	SHH [UCSC Family Browser]
SOURCE	NM_000193
SMD	Hs.164537
SAGE	Hs.164537
GO	patterning of blood vessels [Amigo]  patterning of blood vessels
GO	vasculogenesis [Amigo]  vasculogenesis
GO	metanephros development [Amigo]  metanephros development
GO	ureteric bud branching [Amigo]  ureteric bud branching
GO	cell fate specification [Amigo]  cell fate specification
GO	neural crest cell migration [Amigo]  neural crest cell migration
GO	neural tube formation [Amigo]  neural tube formation
GO	positive regulation of neuroblast proliferation [Amigo]  positive regulation of neuroblast proliferation
GO	osteoblast development [Amigo]  osteoblast development
GO	patched binding [Amigo]  patched binding
GO	protein binding [Amigo]  protein binding
GO	extracellular region [Amigo]  extracellular region
GO	extracellular space [Amigo]  extracellular space
GO	signal transduction [Amigo]  signal transduction
GO	positive regulation of hh target transcription factor activity [Amigo]  positive regulation of hh target transcription factor activity
GO	cell-cell signaling [Amigo]  cell-cell signaling
GO	pattern specification process [Amigo]  pattern specification process
GO	axon guidance [Amigo]  axon guidance
GO	ventral midline development [Amigo]  ventral midline development
GO	salivary gland morphogenesis [Amigo]  salivary gland morphogenesis
GO	hindgut morphogenesis [Amigo]  hindgut morphogenesis
GO	heart development [Amigo]  heart development
GO	androgen metabolic process [Amigo]  androgen metabolic process
GO	peptidase activity [Amigo]  peptidase activity
GO	anterior/posterior pattern formation [Amigo]  anterior/posterior pattern formation
GO	cell surface [Amigo]  cell surface
GO	oligodendrocyte development [Amigo]  oligodendrocyte development
GO	membrane [Amigo]  membrane
GO	intein-mediated protein splicing [Amigo]  intein-mediated protein splicing
GO	spinal cord dorsal/ventral patterning [Amigo]  spinal cord dorsal/ventral patterning
GO	smoothened signaling pathway in regulation of granule cell precursor cell proliferation [Amigo]  smoothened signaling pathway in regulation of granule cell precursor cell proliferation
GO	positive regulation of granule cell precursor proliferation [Amigo]  positive regulation of granule cell precursor proliferation
GO	telencephalon regionalization [Amigo]  telencephalon regionalization
GO	regulation of proteolysis [Amigo]  regulation of proteolysis
GO	lung development [Amigo]  lung development
GO	negative regulation of cell migration [Amigo]  negative regulation of cell migration
GO	male genitalia development [Amigo]  male genitalia development
GO	prostate gland development [Amigo]  prostate gland development
GO	regulation of epithelial cell differentiation [Amigo]  regulation of epithelial cell differentiation
GO	forebrain development [Amigo]  forebrain development
GO	midbrain development [Amigo]  midbrain development
GO	hindbrain development [Amigo]  hindbrain development
GO	hair follicle morphogenesis [Amigo]  hair follicle morphogenesis
GO	negative regulation of proteasomal ubiquitin-dependent protein catabolic process [Amigo]  negative regulation of proteasomal ubiquitin-dependent protein catabolic process
GO	negative regulation of T cell proliferation [Amigo]  negative regulation of T cell proliferation
GO	odontogenesis of dentine-containing tooth [Amigo]  odontogenesis of dentine-containing tooth
GO	embryonic digit morphogenesis [Amigo]  embryonic digit morphogenesis
GO	camera-type eye development [Amigo]  camera-type eye development
GO	laminin-1 binding [Amigo]  laminin-1 binding
GO	tongue morphogenesis [Amigo]  tongue morphogenesis
GO	membrane raft [Amigo]  membrane raft
GO	regulation of transcription [Amigo]  regulation of transcription
GO	negative regulation of cell differentiation [Amigo]  negative regulation of cell differentiation
GO	positive regulation of neuron differentiation [Amigo]  positive regulation of neuron differentiation
GO	positive regulation of transcription from RNA polymerase II promoter [Amigo]  positive regulation of transcription from RNA polymerase II promoter
GO	negative regulation of alpha-beta T cell differentiation [Amigo]  negative regulation of alpha-beta T cell differentiation
GO	embryonic organ development [Amigo]  embryonic organ development
GO	developmental growth [Amigo]  developmental growth
GO	embryonic morphogenesis [Amigo]  embryonic morphogenesis
GO	neuron fate commitment [Amigo]  neuron fate commitment
GO	response to axon injury [Amigo]  response to axon injury
GO	striated muscle cell differentiation [Amigo]  striated muscle cell differentiation
GO	Bergmann glial cell differentiation [Amigo]  Bergmann glial cell differentiation
BIOCARTA	Sonic Hedgehog (SHH) Receptor Ptc1 Regulates cell cycle    [Genes]
BIOCARTA	Sonic Hedgehog (Shh) Pathway    [Genes]
KEGG	Hedgehog signaling pathway
PubGene	SHH
TreeFam	SHH
CTD	6469 [Comparative ToxicoGenomics Database]
	Other databases
Other database	http://www.molgen.mpg.de/research/mundlos/projects_dsh.html
Other database	http://anatomy.med.unsw.edu.au/cbl/embryo/
Other database	http://www.evol.nw.ru/labs/lab38/spirov/hox_pro/shh.html
Other database	http://www.devbio.com/chap06/link0603.shtml
	Probes
Probe	SHH Related clones (RZPD - Berlin)
	PubMed
PubMed	108 Pubmed reference(s) in LocusLink

Bibliography

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PMID 7774016

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PMID 8837770

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PMID 8658135

Two critical periods of Sonic Hedgehog signaling required for the specification of motor neuron identity.

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Cell. 1996 ; 87 (4) : 661-673.

PMID 8929535

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PMID 8681379

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Nature. 1996 ; 384 (6605) : 176-179.

PMID 8906794

Sonic hedgehog differentially regulates expression of GLI and GLI3 during limb development.

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PMID 8948590

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PMID 8971339

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PMID 8790332

Evidence that Shh cooperates with a retinoic acid inducible co-factor to establish ZPA-like activity.

Ogura T, Alvarez IS, Vogel A, Rodrˆ‚guez C, Evans RM, Izpisˆ†a Belmonte JC

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PMID 8625805

Mutations in the human Sonic Hedgehog gene cause holoprosencephaly.

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PMID 8896572

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PMID 8906787

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PMID 8840960

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PMID 9349822

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PMID 9212109

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PMID 9422511

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PMID 10574760

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PMID 10545995

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PMID 10220428

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Chuang PT, McMahon AP

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PMID 10050855

Sonic Hedgehog-induced activation of the Gli1 promoter is mediated by GLI3.

Dai P, Akimaru H, Tanaka Y, Maekawa T, Nakafuku M, Ishii S

The Journal of biological chemistry. 1999 ; 274 (12) : 8143-8152.

PMID 10075717

Sonic hedgehog opposes epithelial cell cycle arrest.

Fan H, Khavari PA

The Journal of cell biology. 1999 ; 147 (1) : 71-76.

PMID 10508856

Sonic hedgehog protein signals not as a hydrolytic enzyme but as an apparent ligand for patched.

Fuse N, Maiti T, Wang B, Porter JA, Hall TM, Leahy DJ, Beachy PA

Proceedings of the National Academy of Sciences of the United States of America. 1999 ; 96 (20) : 10992-10999.

PMID 10500113

Overexpression of ptc1 inhibits induction of Shh target genes and prevents normal patterning in the neural tube.

Goodrich LV, Jung D, Higgins KM, Scott MP

Developmental biology. 1999 ; 211 (2) : 323-334.

PMID 10395791

Expression of sonic hedgehog, patched, and Gli1 in developing taste papillae of the mouse.

Hall JM, Hooper JE, Finger TE

The Journal of comparative neurology. 1999 ; 406 (2) : 143-155.

PMID 10096602

A frequent activated smoothened mutation in sporadic basal cell carcinomas.

Lam CW, Xie J, To KF, Ng HK, Lee KC, Yuen NW, Lim PL, Chan LY, Tong SF, McCormick F

Oncogene. 1999 ; 18 (3) : 833-836.

PMID 9989836

In vivo regulation of somite differentiation and proliferation by Sonic Hedgehog.

Marcelle C, Ahlgren S, Bronner-Fraser M

Developmental biology. 1999 ; 214 (2) : 277-287.

PMID 10525334

Hedgehog controls limb development by regulating the activities of distinct transcriptional activator and repressor forms of Cubitus interruptus.

Mˆ©thot N, Basler K

Cell. 1999 ; 96 (6) : 819-831.

PMID 10102270

The mutational spectrum of the sonic hedgehog gene in holoprosencephaly: SHH mutations cause a significant proportion of autosomal dominant holoprosencephaly.

Nanni L, Ming JE, Bocian M, Steinhaus K, Bianchi DW, Die-Smulders C, Giannotti A, Imaizumi K, Jones KL, Campo MD, Martin RA, Meinecke P, Pierpont ME, Robin NH, Young ID, Roessler E, Muenke M

Human molecular genetics. 1999 ; 8 (13) : 2479-2488.

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Contributor(s)

Written	02-2002	Thierry Magnaldo
		"CNRS, UPR 2169, ""Instabilité Génétique et Cancer"", Institut André LWOFF, 7, rue Guy Moquet, 94801 Villejuif, France"

Citation

This paper should be referenced as such :

Magnaldo T . SHH (Sonic hedgehog). Atlas Genet Cytogenet Oncol Haematol. February 2002 . URL : http://AtlasGeneticsOncology.org/Genes/SHHID378.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Mon Aug 11 21:17:29 2008