The sonic hedgehog gene

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The sonic hedgehog gene is the human form of the hedgehog superfamily of inductive molecules that play a role in the development of the embryo. Sonic hedgehog is important for the development of the front part of the brain, including digits on limbs. This signaling protein helps to establish the line that separates the right and left side of the forebrain. Sonic hedgehog also plays an important role in the formation of the eyes. During early development, the cells that develop into the eye form a single structure called the eye field.  The structure is found in the centre of the developing face. Sonic hedgehog signaling causes the eye field to separate into two distinct eyes (National Library of Medicine, 2020).

The action of the hedgehog gene was first observed in the Drosophila, recent studies have found members of the gene in metazoan, sea urchin, leech, and beetle (Sudhir bar 1995). This is according to an experiment that was done in 1995 which used hybridisation and polymerase chain reaction. This experiment showed a striking similarity in Hh proteins across several species. Evident by the fact that zebrafish Shh was able to activate the signal transduction pathway of the Drosophila.  The hedgehog gene consists of two domains these are; the amino acid domain (Hh-C) where the signalling activity takes place, and the carboxyl Terminal (Hh-C) which is where cleavage takes place and is also known as the sterol recognition regions (SRR)

Hh-C terminal may also be involved in the regulation of the range of amino acids. Autocleavage of the Hh gene turns it into two intermolecular reactions; this cleavage will also allow cholesterol to be added to the amino acid terminal of the Hh gene. The hog domain of the gene can also be split into two regions; the first region is called the Hint, can be seen in both prokaryotes and eukaryotes and is like the self-splicing inteins. When synthesised the Hh proteins are precursor molecules that are 400-460 amino acid long with several different domains. In the Drosophila the carboxyl domain of the gene is globular with inteins. Cestain residue is found on the Beta strands of the Hh proteins, these are very important for auto-processing.

In the Drosophila the Hh gene produces molecules that provide positional information in the embryo and the Imaginal disc. It contains 471 codon open reading frames that can encode a polypeptide of 52,147 long. It is very hydrophobic near the N terminal between 63 and 85 residues. Vertebrae like humans, Zebrafish and chicks have three forms of the hedgehog genes these are; Sonic, Indian and desert. Sonic hedgehog in human is located on the long arm of chromosomal 7q36 it has 155,802,863 to 155,812,272 base pairs (Gilbert SF 2000). The sonic hedgehog gene encodes for the sonic hedgehog proteins that play a role in the formation of the brain, spinal cord, maintenance of the stem cell and eyes (Echelard, Epstein et al. 1993).

It is also an inducer molecule that plays a role in the activation of other transcription factors like Pax and Hox. Which are responsible for the formation of various systems during embryogenesis.  Hedgehog proteins are processed in the endoplasmic reticulum. For example, Shh has processed through its cleavage of the signal peptide and the Autocleavage of Hh processors. The processors are 19Da N- terminal (Shh-N) and 25DaC terminal, signaling activity of the gene is in the N terminal.  The carboxyl-terminal of Shh has intermolecular transferase that is responsible for the attachment of cholesterol; this attachment is what restricts the zone of activity.

Recent studies in mammals have shown that Shh is processed when it binds to a transmembrane receptor called patched. Normally patched inhibits downstream signalling when it’s bound to smoothen. When SHH binds to Patched it releases the seven transmembrane receptors Smoothened from repression. Signalling is through the transcriptional factors GLI and HRK4 which Kruppel related human gene. The malfunction in the signalling pathway has been shown to contribute to the formation of cancers, this is because of the mutation in the gene that codes for Patched causes Gorlin syndrome.

Gorlin syndrome or Nevoid basal carcinoma, is a condition that affects several areas of the body and increases the possibility of an individual developing various cancerous and non-cancerous tumors. Individuals with this illness typically start developing cell carcinomas during adolescent and early adulthood. These cancers most often occur in the face, neck, and back. Individual’s with Gorlin syndrome have a higher risk than the general population of developing other tumors. A small proportion of the affected develop brain tumors called medulloblastoma during childhood (National Library of Medicine, 2020).

References

Echelard, Y., et al. (1993). “Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity.” Cell 75(7): 1417-1430.

Gilbert SF (2000). Developmental Biology. 6th edition.

Sudhir bar, K. r. t. A. B., Zhi-Chun Lai, (1995). “Evolution of the hedgehog Gene Family.” Genetics Society of America.

Reference, G. H. (n.d.-a). Gorlin syndrome. Genetics Home Reference. Retrieved May 14, 2020, from https://ghr.nlm.nih.gov/condition/gorlin-syndrome

Reference, G. H. (n.d.-b). SHH gene. Genetics Home Reference. Retrieved May 14, 2020, from https://ghr.nlm.nih.gov/gene/SHH

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