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Sonic hedgehog

Sonic hedgehog homolog (Drosophila)
3D structure of the signaling domain of the murine Sonic hedgehog from PDB 1vhh
Available structures: 1vhh
Symbol(s) SHH; HHG1; HLP3; HPE3; SMMCI
External IDs OMIM: 600725 MGI: 98297 Homologene: 30961
RNA expression pattern

More reference expression data

Human Mouse
Entrez 6469 20423
Ensembl ENSG00000164690 ENSMUSG00000002633
Uniprot Q15465 Q8C765
Refseq NM_000193 (mRNA)
NP_000184 (protein)
NM_009170 (mRNA)
NP_033196 (protein)
Location Chr 7: 155.29 - 155.3 Mb Chr 5: 28.79 - 28.8 Mb
Pubmed search [1] [2]

Sonic hedgehog homolog (SHH) is one of three proteins in the mammalian hedgehog family, 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.



The hedgehog gene (hh) was first identified in the classic Heidelberg screens of Eric Wieschaus and Christiane Nusslein-Volhard, as published in 1978. These screens, which led to their winning the Nobel Prize in 1995 along with developmental geneticist Edward B. Lewis, identified genes that control the segmentation pattern of Drosophila melanogaster (fruit fly) embryos. The hh loss of function mutant phenotype causes the embryos to be covered with denticles (small pointy projections), much like a hedgehog.

Investigations aimed at finding a hedgehog equivalent in mammals revealed three homologous genes. The first two discovered, desert hedgehog and Indian hedgehog, were named for species of hedgehogs, while sonic hedgehog was named after Sega's video game character Sonic the Hedgehog.[1] In zebrafish, the orthologues of the three mammalian hh genes are: shh a, shh b (formerly described as tiggywinkle hedgehog named for a character from Beatrix Potter's books for children.), and indian hedgehog b (formerly described as echidna hedgehog, named for the spiny anteater).


Of the hh homologues, shh has been found to have the most critical roles in development, acting as a morphogen involved in patterning many systems, including the limb[2] and midline structures in the brain[3] and spinal cord[4] and the thalamus by the zona limitans intrathalamica[5]. Mutations in the human sonic hedgehog gene, SHH, cause holoprosencephaly type 3 (HPE3) as a result of the loss of the ventral midline. Sonic hedgehog is secreted by the zone of polarizing activity (ZPA), which is located on posterior side of a limb bud in an embryo. The sonic hedgehog transcription pathway has also been linked to the formation of specific kinds of cancerous tumours.

More recently, sonic hedgehog has also been shown to act as an axonal guidance cue. It has been demonstrated that Shh attracts commissural axons at the ventral midline of the developing spinal cord.[6] Specifically, Shh attracts retinal ganglion cell (RGC) axons at low concentrations and repels them at higher concentrations.[7] The absence (non-expression) of Shh has been shown to control the growth of nascent hind limbs in cetaceans[8] (whales and dolphins).


  SHH undergoes a series of processing steps before it is secreted from the cell. Newly synthesised SHH weighs 45 kDa and is referred to as the preproprotein. As a secreted protein it contains a short signal sequence at its N-terminus, which is recognised by the signal recognition particle during the translocation into the endoplasmic reticulum (ER), the first step in protein secretion. Once translocation is complete, the signal sequence is removed by signal peptidase in the ER. There SHH undergoes autoprocessing to generate a 20 kDa N-terminal signaling domain (SHH-N) and a 25 kDa C-terminal domain with no known signaling role.[9] The cleavage is catalysed by a protease within the C-terminal domain. During the reaction, a cholesterol molecule is added to the C-terminus of SHH-N.[10] Thus the C-terminal domain acts as an intein and a cholesterol transferase. Another hydrophobic moiety, a palmitate, is added to the alpha-amine of N-terminal cysteine of SHH-N. This modification is required for efficient signaling, resulting in 30-fold increase in potency over the non-palmitylated form.[11]


Some clinicians and scientists criticize giving genes frivolous or quirky names, calling it inappropriate that patients with "a serious illness or disability are told that they or their child have a mutation in a gene such as Sonic hedgehog."[12]

See also

  • Zbtb7, a gene which was originally named Pokemon after the video game Pokémon

Further reading

  • Dorus S, Anderson JR, Vallender EJ, et al (2006). "Sonic Hedgehog, a key development gene, experienced intensified molecular evolution in primates". Hum. Mol. Genet. 15 (13): 2031-7. doi:10.1093/hmg/ddl123. PMID 16687440.
  • Gilbert, Scott F. (2000). Developmental biology, 6th edition, Sunderland, Mass: Sinauer Associates. ISBN 0-87893-243-7. 
  • Kim J, Kim P, Hui CC (2001). "The VACTERL association: lessons from the Sonic hedgehog pathway.". Clin. Genet. 59 (5): 306-15. PMID 11359461.
  • Nanni L, Ming JE, Du Y, et al. (2001). "SHH mutation is associated with solitary median maxillary central incisor: a study of 13 patients and review of the literature.". Am. J. Med. Genet. 102 (1): 1-10. PMID 11471164.
  • Mullor JL, Sánchez P, Altaba AR (2003). "Pathways and consequences: Hedgehog signaling in human disease.". Trends Cell Biol. 12 (12): 562-9. PMID 12495844.
  • Williams JA (2006). "Hedgehog and spinal cord injury.". Expert Opin. Ther. Targets 9 (6): 1137-45. doi:10.1517/14728222.9.6.1137. PMID 16300466.
  • Morton JP, Lewis BC (2007). "Shh signaling and pancreatic cancer: implications for therapy?". Cell Cycle 6 (13): 1553-7. PMID 17611415.


  1. ^ Anwood, Robert (2007-09-06). Emus Can't Walk Backwards. Ebury Press, 113-114. ISBN 9780091921514. 
  2. ^ Currie P.D. and Ingham P.W. (1996). "Induction of a specific muscle cell type by a hedgehog-like protein in zebrafish". Nature 382 (6590): 452-5. doi:10.1038/382452a0. PMID 8684485.
  3. ^ Herzog W, Zeng X, Lele Z, Sonntag C, Ting JW, Chang CY, Hammerschmidt M (2003). "Adenohypophysis formation in the zebrafish and its dependence on sonic hedgehog". Dev. Biol. 254 (1): 36-49. PMID 12606280.
  4. ^ Lewis KE, Eisen JS (2001). "Hedgehog signaling is required for primary motoneuron induction in zebrafish". Development 128 (18): 3485-95. PMID 11566854.
  5. ^ Scholpp S, Wolf O, Brand M, Lumsden A (2006). "Hedgehog signalling from the zona limitans intrathalamica orchestrates patterning of the zebrafish diencephalon". Development 133 (5): 855-64. doi:10.1242/dev.02248. PMID 16452095.
  6. ^ F. Charron, E. Stein, J. Jeong, A. McMahon, M. Tessier-Lavigne. "The morphogen sonic hedgehog is an axonal chemoattractant that collaborates with netrin-1 in midline axon guidance.". CELL. 2003. 113:11-23.
  7. ^ Kolpak A, Zhang J, Bao ZZ (2005). "Sonic hedgehog has a dual effect on the growth of retinal ganglion axons depending on its concentration". J. Neurosci. 25 (13): 3432-41. doi:10.1523/JNEUROSCI.4938-04.2005. PMID 15800198.
  8. ^ Thewissen JG, Cohn MJ, Stevens LS, Bajpai S, Heyning J, Horton WE (2006). "Developmental basis for hind-limb loss in dolphins and origin of the cetacean bodyplan". Proc. Natl. Acad. Sci. U.S.A. 103 (22): 8414-8. doi:10.1073/pnas.0602920103. PMID 16717186.
  9. ^ Bumcrot DA, Takada R and McMahon AP (1995). "Proteolytic processing yields two secreted forms of sonic hedgehog". Mol Cell Biol. 15 (4): 2294-2303. PMID 7891723.
  10. ^ Porter JA, Young KE and Beachy PA (1996). "Cholesterol modification of hedgehog signaling proteins in animal development". Science 274 (5285): 255-259. PMID 8824192.
  11. ^ Pepinsky RB, Zeng C, Wen D, Rayhorn P, Baker DP, Williams KP, Bixler SA, Ambrose CM, Garber EA, Miatkowski K et al (1998). "Identification of a palmitic acid-modified form of human Sonic hedgehog". J Biol Chem 273 (22): 14037-14045. PMID 9593755.
  12. ^ Maclean K. (2006). "Humour of gene names lost in translation to patients". Nature 439 (7074): 266. doi:10.1038/439266d. PMID 16421543.
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Sonic_hedgehog". A list of authors is available in Wikipedia.
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