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, for example, the growth of digits on limbs and organisation 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.

Some clinicians and scientists criticise 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."

Discovery

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The hedgehog gene (hh) was first identifed in the classic Heidelberg screens of Eric Wieschaus and Christiane Nusslein-Volhard, as published in 1978. These screens, which led to their both winning the Nobel Prize in 1995, 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. In addition to orthologues of the three mammalian hh genes, zebrafish have two further homologues: echidna hedgehog, named for the eponymous spiny anteater, and tiggywinkle hedgehog named for a character from Beatrix Potter's books for children.

Function

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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 and midline structures in the brain and spinal cord. 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. Specifically, it attracts retinal ganglion cell (RGC) axons at low concentrations and repels them at higher concentrations. The absence (non-expression) of Shh has been shown to control the growth of nascent hind limbs in cetaceans (whales and dolphins).

Processing

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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. 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. Thus the C-terminal domain acts as an intein and a cholesterol transferase. Anther 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.

See also

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

External links

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• An introductory article on shh

References

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Proteins | Morphogens

ソニック・ヘッジホッグ