Criticisms of �Sonic Hedgehog� Bibliography
As scientists began to focus more on the human genome, they also began to look for a potential mammalian homolog to the fruit fly hedgehog gene (which at the time seemed highly probable because evolution is a conservative process). Ultimately, the investigations would lead to the finding of three orthologous mammalian hedgehog genes, each responsible for a cell signaling pathways similar to that of the fruit fly cognate. The new discoveries would be named �desert hedgehog,� �indian hedgehog,� and �Sonic hedgehog� (which was named after the Sega videogame character).
Many groups immediately began to clone and study the various hedgehog genes, especially Sonic. It was already known that the protein product of the gene somehow triggered a cell signaling pathway which ends in the organization and formation of various embryonic tissues.
In 1992, a group led by Dr. Philip Beachy of Johns Hopkins School of Medicine exposed the intriguing biochemical properties of the shh (Sonic hedgehog) protein product. They discovered that an original 45 kD precursor undergoes an autocatalytic processing reaction virtually unprecedented in the study of protein modification. During the translation of the gene, a signal sequence located on the N-terminus of the newly forming protein commences a relocation of the ribosomal complex to the Endoplasmic Reticulum (ER). Once inside the ER lumen, the 45 kD product is split into a 20 kD N-terminal domain which would soon be attributed as a signaling molecule and a 25 kD C-teminal domain which acts as a protease in the cleavage of the original precursor. Cholesterol plays imperative roles in the process. The steroid molecule acts as a coenzyme (organic cofactor) during the initial splitting of the molecule by binding to the C-terminal domain, which further acts as a cholesterol transferase by then adding that same cholesterol molecule to the N-terminal domain, rendering it fully processed and activated. Evidence has recently appeared that the defective cholesterol synthesis characteristic of Smith-Lemli-Opitz syndrome may be caused by the steroid�s role in such modifications (Howard Hughes Medical Institution, 2008).
Groups such as Beachy�s then began to focus on the function of the modified shh signaling molecule. With the foreknowledge that shh is in part responsible for nervous system development, Beachy and his colleagues exposed dissected parts of an embryonic chick nervous system to the shh protein. It was found that cells typical to the midline of the body differentiated to high protein concentrations while cells that arise away from the midline respond to lower concentrations of shh. It was then concluded that based on the expression of shh genes in restricted locations, a graded response to the shh protein coordinates patterns of cellular proliferation and differentiation in various organs (i.e. shh concentrations throughout various checkpoints in nerve development were proven to drive the differentiation of neurons into the various subcategories of motor-, inter-, and sensory neurons). The next step was to then map out the signal transduction pathway which starts with the N-terminal shh protein.
Work on the �Hedgehog Pathway� returned to the fruit fly in 1996 when the pair of Chen and Struhl provided evidence of a hh protein receptor called Patched (Ptc). The signaling mechanism they suggested starts when hh (or shh) binds to a Ptc, which is already pre-connected to a molecule called Smoothened (Smo) in a Ptc-Smo complex. The binding of the hh protein to the receptor complex initiates the release of Smo which relays a message that will initiate a cellular response. Various shh binding studies would eventually prove this model.
Aside from nervous system development, shh plays a role in the formation of embryonic limb buds. In a series of 1999 studies on mice with null mutations of the shh gene, it was proven that shh signaling is required for the normal functioning of the complex pathway which leads to limb development (Imokawa et al., 1997).
The signaling protein was recently shown to be a chemoattractant through studies of developing chicks as shh plays a role in directing the actual placement of neurons and organs throughout the body and it is highly responsible for the left-right asymmetry of bodily organs. Shh is also vital in the embryonic organization of the visual system, as well as the homeostasis of several tissues throughout an individual�s entire life (unfortunately making shh a proto-oncogene) (Online Mendelian Inheritance in Man, 2008).
Further Reading: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600725
This web page was produced as an assignment for an AP Biology course at Montgomery High School.