Sonic hedgehog protein
Morphogen that patterns embryonic development via concentration gradients.
Sonic hedgehog protein, produced by the SHH gene, is a crucial signaling molecule in the embryonic development of planulozoan animals. It directs morphogenesis by organizing the central nervous system, limbs, digits, and numerous other body structures. As a morphogen, it patterns the growing embryo through a concentration gradient, following the French flag model: different concentrations of SHH instruct cells to adopt distinct fates.
The hedgehog gene was first discovered in fruit flies during the 1980 Heidelberg screens by Christiane Nüsslein-Volhard and Eric Wieschaus, work that later earned them a Nobel Prize. Mutant fly embryos lacking this gene were covered in denticles, small spike-like projections resembling a hedgehog’s spines. When researchers searched for vertebrate counterparts, they found three related genes. Two were named after hedgehog species—desert hedgehog and Indian hedgehog—while the third was dubbed sonic hedgehog after the video game character. Robert Riddle, a postdoctoral fellow at the Tabin Lab, chose the name after his wife brought home a magazine featuring an ad for the first Sonic the Hedgehog game. In zebrafish, two of the three vertebrate hedgehog genes are duplicated: SHH a and SHH b (originally called tiggywinkle hedgehog, after a Beatrix Potter character), along with ihha and ihhb (formerly echidna hedgehog, named for the spiny anteater, not the Sonic character).
Among the hedgehog homologues, SHH plays the most critical developmental roles. It acts as a morphogen to pattern many systems, including the anterior pituitary, brain pallium, spinal cord, lungs, teeth, and the thalamus via the zona limitans intrathalamica. In vertebrates, limb and digit development depends on SHH secreted by the zone of polarizing activity on the posterior side of the embryonic limb bud. Fibroblast growth factors from the apical ectodermal ridge must be present for SHH to be expressed in developing limb buds. SHH also guides axons: it attracts commissural axons at the ventral midline of the developing spinal cord and both attracts and repels retinal ganglion cell axons depending on concentration. The absence of SHH controls the growth of nascent hind limbs in cetaceans like whales and dolphins.
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Lore & Background
The hedgehog gene (hh) was first identified in the fruit fly Drosophila melanogaster in the classic Heidelberg screens of Christiane Nüsslein-Volhard and Eric Wieschaus, published in 1980. The hh loss-of-function mutant phenotype causes embryos to be covered with denticles resembling hedgehog spikes. Investigations aimed at finding a hedgehog equivalent in vertebrates by Philip Ingham, Andrew P. McMahon, and Clifford Tabin revealed three homologous genes. Two were named for hedgehog species—desert hedgehog and Indian hedgehog—while sonic hedgehog was named after the video game character Sonic the Hedgehog by Robert Riddle, a postdoctoral fellow at the Tabin Lab, after his wife Betsy Wilder brought home a magazine with an advert for the first game in the series.
Reader's Guide
Sonic hedgehog protein is essential for vertebrate development, acting as a morphogen that patterns many systems including the anterior pituitary, pallium of the brain, spinal cord, lungs, teeth, and thalamus. In the developing limb, SHH is secreted by the zone of polarizing activity on the posterior side of the embryonic limb bud. Mutations in the human SHH gene cause holoprosencephaly type 3 (HPE3), a failure of the cerebral hemispheres to split, as demonstrated in SHH knock-out mice where the forebrain midline failed to develop and only a single fused telencephalic vesicle resulted. SHH also plays roles in adult tissue differentiation, proliferation, and maintenance, and abnormal activation of SHH signaling is implicated in various cancers including breast, skin, brain, liver, and gallbladder. The protein functions as a vital morphogenic signaling molecule, contributing to cell growth, specification, and body plan organization, and is considered an essential gene for development.
Did You Know?
- Mutations in the SHH gene can cause holoprosencephaly, a failure of splitting in the cerebral hemispheres.
- SHH attracts retinal ganglion cell axons at low concentrations and repels them at higher concentrations.
- The absence of SHH expression controls the growth of nascent hind limbs in cetaceans (whales and dolphins).
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