Sonic Hedgehog: Master Gene for Embryogenesis
المؤلف:
T.W. Sadler
المصدر:
Langmans Medical Embryology
الجزء والصفحة:
14th E, p8-10
2025-05-21
336
In the days before molecular biology, embryologists were convinced of the existence of a master signal that directed all of embryonic development. This signal would act as a morphogen, a secreted molecule that would establish concentration gradients and instruct cells in how to become different tissues and organs. Al though we now know that there are a multitude of signaling molecules that coordinately regulate development, the protein SHH comes closest to being the master morphogen of them all. This protein is involved in development of the vasculature, left—right axis formation, midline, cere bellum, neural patterning, limbs, smooth muscle patterning, heart, gut, pharynx, lungs, pancreas, kidneys, bladder, hair follicles, teeth, thymocytes, inner ear, eyes, and taste buds: a veritable plethora of developmental events. Sonic signaling is via the pathway shown in Figure 1.
Fig1. Drawings illustrating the sonic hedgehog [SHH] signaling pathway. A. Drawing of a cell showing Patched inhibition of Smoothened that blocks activation of the GLI proteins that normally transduce the SHH signal. B. Drawing showing SHH binding to its receptor Patched, that removes Patched’s inhibition of Smoothened. Activation of Smoothened then upregulates the GLI transcription factors that bind to DNA and control downstream effector genes in the SHH pathway.
The protein binds to its receptor Patched (Ptc), a protein that normally inhibits the receptor-like protein Smoothened (Smo). Upon binding of SHH to Ptc, Ptc activity is eliminated, the in hibition of Smo is removed, and Smo is activated to, ultimately, upregulate activity of the GLI family (1 to 3) of transcription factors that control expression of target genes. The specificity of SHH expression in different cell types is regulated by multiple enhancer elements acting independently to control SHH transcription in different cells and tissues.
The SHH protein has some unique characteristics, including the fact that after translation, it is cleaved and cholesterol is added to the C-terminus of its N-terminal domain. It is the addition of cholesterol that links SHH to the plasma membrane. Then, a palmitic acid moiety is added to the N-terminus and SHH becomes fully functional. Its release from the plasma membrane is produced by the transmembrane protein Dispatched, and at this point, SHH can establish the concentration gradients characteristic of its action as a morphogen.
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