The Sonic Hedgehog Gene

 

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. 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 the species.

This was shown 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).


Patterning of the Embryo 



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 similar to 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 autoprocessing.

In the Drosophila the Hh gene secrets molecules that provide positional information in the embryo and the Imarginal disc, it contains 471 codon open reading frames that are able to 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 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, signalling 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 cancer, this is because of the mutation in the gene that codes for patched causes Gorlin syndrome.

 

 

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.

 

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