Sonic hedgehog
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| Sonic hedgehog homolog (Drosophila)
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| Image:Shh structure.png | ||||||||||||||||||||||||||||||||||||||
| 3D structure of the signaling domain of the murine Sonic hedgehog from PDB 1vhh | ||||||||||||||||||||||||||||||||||||||
| Available structures: For the file format that describes the 3D structures of molecules found in the Protein Data Bank, see Protein Data Bank (file format).
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| Identifiers | ||||||||||||||||||||||||||||||||||||||
| Symbol(s) | SHH; HHG1; HLP3; HPE3; SMMCI | |||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 600725 MGI: 98297 Homologene: 30961 | |||||||||||||||||||||||||||||||||||||
| RNA expression pattern | ||||||||||||||||||||||||||||||||||||||
| Orthologs | ||||||||||||||||||||||||||||||||||||||
| 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 | [5] | [6] | ||||||||||||||||||||||||||||||||||||
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.
Discovery
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).
Function
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[1] and midline structures in the brain[1] and spinal cord[1] and the thalamus by the zona limitans intrathalamica[1]. 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.[1] Specifically, Shh attracts retinal ganglion cell (RGC) axons at low concentrations and repels them at higher concentrations.[1] The absence (non-expression) of Shh has been shown to control the growth of nascent hind limbs in cetaceans[1] (whales and dolphins).
Processing
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.[1] 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.[1] 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.[1]
Criticism of the name
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."[1]
See also
References
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. doi:10.1034/j.1399-0004.2001.590503.x. 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. doi:10.1002/1096-8628(20010722)102:1%3C1::AID-AJMG1336%3E3.0.CO;2-U. 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.
External links
- An introductory article on shh at Davidson College
- SHH at The GDB Human Genome Database
- Rediscovering biology: Unit 7, Genetics of development. Expert interview transcripts, interview with John Incardona, PhD. explanation of the discovery and naming of the sonic hedgehog gene
- ‘Sonic Hedgehog’ sounded funny, at first. New York Times, November 12, 2006.
Animal intercellular signaling peptides and proteins | |
|---|---|
| Growth factors | Epidermal growth factor - Fibroblast growth factor (FGF2) - Nerve growth factor - Platelet-derived growth factor - Transforming growth factor (TGFα, TGFβ, TGFβ pathway) |
| Other | Hedgehog (Sonic hedgehog) - Integrin - JAK/STAT (JAK/STAT) - MAPK/ERK pathway (MAPK/ERK) - NF-κB - Notch (1, 2, 3) - p53 - Wnt (WNT4, Frzb) |
ja:ソニック・ヘッジホッグsv:Sonic hedgehog
Acknowledgement and Attribution Regarding Sources of Content
Some of the initial content on this page may be incorporated in part from copyleft sources in the public domain including wikis such as Wikipedia and AskDrWiki. Drug information for patients came from the The National Library of Medicine. Infectious disease information may have come from the Centers for Disease Control (CDC). Differential Diagnoses are drawn from clinicians as well as an amalgamation of 3 sources: 1.The Disease Database; 2. Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:3; 3. Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:7 .
