Sonic hedgehog

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. [cite book|last=Anwood|first=Robert|authorlink=Robert Anwood|title=Emus Can't Walk Backwards|publisher=Ebury Press|date=2007-09-06|pages=113-114|isbn=9780091921514] In zebrafish, the orthologues of the three mammalian hh genes are: [http://zfin.org/cgi-bin/webdriver?MIval=aa-markerview.apg&OID=ZDB-GENE-980526-166 shh a] , [http://zfin.org/cgi-bin/webdriver?MIval=aa-markerview.apg&OID=ZDB-GENE-980526-41 shh b] (formerly described as "tiggywinkle hedgehog" named for a character from Beatrix Potter's books for children.), and [http://zfin.org/cgi-bin/webdriver?MIval=aa-markerview.apg&OID=ZDB-GENE-980526-135 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 limbcite journal |author=Currie P.D. and Ingham P.W. |title=Induction of a specific muscle cell type by a hedgehog-like protein in zebrafish |journal=Nature |volume=382 |issue=6590 |pages=452–5 |year=1996 |pmid=8684485 |doi=10.1038/382452a0] and midline structures in the braincite journal |author=Herzog W, Zeng X, Lele Z, Sonntag C, Ting JW, Chang CY, Hammerschmidt M |title=Adenohypophysis formation in the zebrafish and its dependence on sonic hedgehog |journal=Dev. Biol. |volume=254 |issue=1 |pages=36–49 |year=2003 |pmid=12606280 |doi=10.1016/S0012-1606(02)00124-0] and spinal cordcite journal |author=Lewis KE, Eisen JS |title=Hedgehog signaling is required for primary motoneuron induction in zebrafish |journal=Development |volume=128 |issue=18 |pages=3485–95 |year=2001 |pmid=11566854] and the thalamus by the zona limitans intrathalamicacite journal |author=Scholpp S, Wolf O, Brand M, Lumsden A |title=Hedgehog signalling from the zona limitans intrathalamica orchestrates patterning of the zebrafish diencephalon |journal=Development |volume=133 |issue=5 |pages=855–64 |year=2006 |url=http://dev.biologists.org/cgi/content/full/133/5/855 |pmid=16452095 |doi=10.1242/dev.02248] . 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.cite journal |author=F. Charron, E. Stein, J. Jeong, A. McMahon, M. Tessier-Lavigne |title=The morphogen sonic hedgehog is an axonal chemoattractant that collaborates with netrin-1 in midline axon guidance|journal=Cell. 2003. 113:11-23] Specifically, Shh attracts retinal ganglion cell (RGC) axons at low concentrations and repels them at higher concentrations.cite journal |author=Kolpak A, Zhang J, Bao ZZ |title=Sonic hedgehog has a dual effect on the growth of retinal ganglion axons depending on its concentration |journal=J. Neurosci. |volume=25 |issue=13 |pages=3432–41 |year=2005 |pmid=15800198 |doi=10.1523/JNEUROSCI.4938-04.2005] The absence (non-expression) of Shh has been shown to control the growth of nascent hind limbs in cetaceanscite journal |author=Thewissen JG, Cohn MJ, Stevens LS, Bajpai S, Heyning J, Horton WE |title=Developmental basis for hind-limb loss in dolphins and origin of the cetacean bodyplan |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=103 |issue=22 |pages=8414–8 |year=2006 |pmid=16717186 |doi=10.1073/pnas.0602920103] (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.cite journal| author=Bumcrot DA, Takada R and McMahon AP | year=1995 | title=Proteolytic processing yields two secreted forms of sonic hedgehog | journal=Mol Cell Biol. | volume=15 | issue=4 | pages=2294–2303 |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?pubmedid=7891723 |pmid=7891723] 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.cite journal| author=Porter JA, Young KE and Beachy PA | year=1996 | title=Cholesterol modification of hedgehog signaling proteins in animal development | journal=Science | volume=274 | issue=5285 | pages=255–259 |pmid=8824192| doi=10.1126/science.274.5285.255] 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.cite journal| author=Pepinsky RB, Zeng C, Wen D, Rayhorn P, Baker DP, Williams KP, Bixler SA, Ambrose CM, Garber EA, Miatkowski K "et al" | year=1998 | title=Identification of a palmitic acid-modified form of human Sonic hedgehog | journal=J Biol Chem | volume=273 | issue=22 | pages=14037–14045 |url=http://www.jbc.org/cgi/content/full/273/22/14037 |pmid=9593755| doi=10.1074/jbc.273.22.14037]

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"."cite journal |author=Maclean K. |title=Humour of gene names lost in translation to patients |journal=Nature |volume=439 |issue=7074 |pages=266 |year=2006 |pmid=16421543 |doi=10.1038/439266d]

ee also

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

References

Further reading

*cite journal |author=Dorus S, Anderson JR, Vallender EJ, "et al" |title=Sonic Hedgehog, a key development gene, experienced intensified molecular evolution in primates |journal=Hum. Mol. Genet. |volume=15 |issue=13 |pages=2031–7 |year=2006 |pmid=16687440 |doi=10.1093/hmg/ddl123
*cite book |author=Gilbert, Scott F. |title=Developmental biology |publisher=Sinauer Associates |location=Sunderland, Mass |edition=6th edition |year=2000 |isbn=0-87893-243-7
*cite journal | author=Kim J, Kim P, Hui CC |title=The VACTERL association: lessons from the Sonic hedgehog pathway |journal=Clin. Genet. |volume=59 |issue= 5 |pages= 306–15 |year= 2001 |pmid= 11359461| doi=10.1034/j.1399-0004.2001.590503.x
*cite journal | author=Morton JP, Lewis BC |title=Shh signaling and pancreatic cancer: implications for therapy? |journal=Cell Cycle |volume=6 |issue= 13 |pages= 1553–7 |year= 2007 |pmid= 17611415 |doi=
*cite journal | author=Mullor JL, Sánchez P, Altaba AR |title=Pathways and consequences: Hedgehog signaling in human disease |journal=Trends Cell Biol. |volume=12 |issue= 12 |pages= 562–9 |year= 2003 |pmid= 12495844 |doi=
*cite journal | author=Nanni L, Ming JE, Du Y, "et al." |title=SHH mutation is associated with solitary median maxillary central incisor: a study of 13 patients and review of the literature |journal=Am. J. Med. Genet. |volume=102 |issue= 1 |pages= 1–10 |year= 2001 |pmid= 11471164| doi=10.1002/1096-8628(20010722)102:1<1::AID-AJMG1336>3.0.CO;2-U
*cite journal | author=Williams JA |title=Hedgehog and spinal cord injury |journal=Expert Opin. Ther. Targets |volume=9 |issue= 6 |pages= 1137–45 |year= 2006 |pmid= 16300466 |doi= 10.1517/14728222.9.6.1137

External links

* [http://www.bio.davidson.edu/Courses/Molbio/MolStudents/spring2003/Watson/Sonichedgehog.htm An introductory article on "shh"] at Davidson College
* [http://www.gdb.org/gdb-bin/genera/genera/hgd/GenomicSegment?!action=query&displayName=shh SHH at The GDB Human Genome Database]
* [http://www.learner.org/channel/courses/biology/units/gendev/experts/incardona.html 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
* [http://www.nytimes.com/2006/11/12/weekinreview/12schwartz.html ‘Sonic Hedgehog’ sounded funny, at first] . New York Times, November 12, 2006.

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