Mutations in this gene can cause holoprosencephaly, a failure of splitting in the cerebral hemispheres,[7] as demonstrated in an experiment using SHH knock-out mice in which the forebrain midline failed to develop and instead only a single fused telencephalic vesicle resulted.

Abnormal activation of SHH signaling in adult tissues has been implicated in various types of cancers including breast, skin, brain, liver, gallbladder and many more.

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, as published in 1980.

[10] These screens, which led to the researchers winning a Nobel Prize in 1995 along with developmental geneticist Edward B. Lewis, identified genes that control the segmentation pattern of the Drosophila embryos.

The hh loss of function mutant phenotype causes the embryos to be covered with denticles, i.e. small pointy projections resembling the spikes of a hedgehog.

Investigations aimed at finding a hedgehog equivalent in vertebrates by Philip Ingham, Andrew P. McMahon and Clifford Tabin revealed three homologous genes.

[15][16] The gene was named by Robert Riddle, a postdoctoral fellow at the Tabin Lab, after his wife Betsy Wilder came home with a magazine containing an advert for the first game in the series, Sonic the Hedgehog (1991).

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 anterior pituitary,[23] pallium of the brain,[24] spinal cord,[25] lungs,[26] teeth[27] and the thalamus by the zona limitans intrathalamica.

[13] Mutations in the human sonic hedgehog gene SHH cause holoprosencephaly type 3 HPE3, as a result of the loss of the ventral midline.

[32] For SHH to be expressed in the developing embryo limbs, a morphogen called fibroblast growth factors must be secreted from the apical ectodermal ridge.

[39] This protein functions as a vital morphogenic signaling molecule and plays an important role in the formation of many different structures in developing embryos.

The sonic hedgehog (SHH) signaling molecule assumes various roles in patterning the central nervous system (CNS) during vertebrate development.

[41] The notochord—a structure derived from the axial mesoderm—produces SHH, which travels extracellularly to the ventral region of the neural tube and instructs those cells to form the floor plate.

[45] Studies involving ectopic expression of SHH in vitro[46] and in vivo[47] result in floor plate induction and differentiation of motor neuron and ventral interneurons.

[47] Once the floor plate is established, cells residing in this region will subsequently express SHH themselves,[50] generating a concentration gradient within the neural tube.

[52] In vitro studies show that incremental two- and threefold changes in SHH concentration give rise to motor neuron and different interneuronal subtypes as found in the ventral spinal cord.

[54] Graded SHH signaling is suggested to be mediated through the Gli family of proteins, which are vertebrate homologues of the Drosophila zinc-finger-containing transcription factor Cubitus interruptus (Ci).

Depending upon the nature of their interaction with SHH, they are classified into two groups—class I and class II—and are composed of members from the Pax, Nkx, Dbx and Irx families.

In vertebrates, SHH signaling in the ventral portion of the neural tube is most notably responsible for the induction of floor plate cells and motor neurons.

[68] The spatial and temporal aspect of the progressive induction of genes and cell fates in the ventral neural tube is illustrated by the expression domains of two of the most well-characterized transcription factors, Olig2 and Nkx2.2.

[68] Early in development, the cells at the ventral midline have only been exposed to a low concentration of SHH for a relatively short time and express the transcription factor Olig2.

[73] SHH in particular is needed for growth of epithelial cervical loops, where the outer and inner epitheliums join and form a reservoir for dental stem cells.

The secondary enamel knots secrete SHH in combination with other signaling molecules to thicken the oral ectoderm and begin patterning the complex shapes of the crown of a tooth during differentiation and mineralization.

By modulating retinoblastoma protein activity in rat cochlea, sonic hedgehog allows mature hair cells that normally cannot return to a proliferative state to divide and differentiate.

Specifically, SHH induces dermal angiogenesis by acting directly on adipocyte precursors and promoting their proliferation through their expression of the peroxisome proliferator-activated receptor γ (Pparg) gene.

This modification is required for efficient signaling, resulting in a 30-fold increase in potency over the non-palmitylated form and is carried out by a member of the membrane-bound O-acyltransferase family Protein-cysteine N-palmitoyltransferase HHAT.

[89] The gene has been linked to a condition known as holoprosencephaly, which can result in severe brain, skull and facial defects, causing a few clinicians and scientists to criticize the name on the grounds that it sounds too frivolous.

[17][90][91] This controversy has largely died down, and the name is now generally seen as a humorous relic of the time before the rise of fast, cheap complete genome sequencing and standardized nomenclature.

[92] The problem of the "inappropriateness" of the names of genes such as "Mothers against decapentaplegic," "Lunatic fringe," and "Sonic hedgehog" is largely avoided by using standardized abbreviations when speaking with patients and their families.