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Researchers Discover Mechanism Of Cleft Palate Development

Researchers led by a team of UC San Francisco scientists have identified the mechanism by which a disfiguring birth defect wreaks its havoc. Cleft palate, the most common craniofacial birth defect in humans, occurs when the two sides of the palate do not properly fuse during fetal development, leaving an opening or cleft in the roof of the mouth.

Earlier research had already established that abnormalities in the gene for Transforming Growth Factor Alpha (TGF-a) were linked to cleft lip and palate syndromes. TGF-a is a growth factor with many known functions yet how it related to cleft palate was a mystery until now.

The inter-institutional group, led by Rik Derynck, PhD, UCSF professor of cell biology in the Department of Growth & Development, and Zena Werb, PhD, UCSF professor of cell biology in the Department of Anatomy, demonstrated that during normal embryonic development, docking of the molecule TGF-a with the Epidermal Growth Factor Receptor (EGFR), results in the production of a class of proteins called matrix metalloproteinases (MMPs).

Using "genetic knock-out" mice specially bred without the EGFR, the researchers learned that after activation of the EGFR, MMPs regulate the closure of the palate. Palate closure must be closely coordinated with the development of the lower jaw, a process regulated by MMPs. Simply put, if EGFR does not function properly when TGF-a joins with it, MMPs are not produced and cleft palates frequently result. The study is reported in the May 1999 issue of the journal Nature Genetics.

"This study has provided a developmental basis for the correlation between EGFR functioning and cleft palate syndrome but also illuminates the development mechanism for palate closure," says Derynck. "The role of this receptor in palate closure is through its ability to induce the activity of proteases. This is an intriguing finding because we believe that this animal study will translate very closely to humans."

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Contact: James Larkin
jlarkin@pubaff.ucsf.edu
415-750-6633
University of California - San Francisco
1-May-1999


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