Using Frog Faces to Better Understand Clefts in the Primary Palate

Virginia Commonwealth University, Richmond VA

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Abstract

DESCRIPTION (provided by applicant): Most research concerning the face focuses on the secondary palate, while relatively less is known about the primary palate. Therefore, the broad goals of the lab are to fill this significant knowledge gap in the field and further our understanding of primary palate formation and defects concerning this structure such as median orofacial clefts. To do so we have developed an innovative model system using Xenopus laevis to study orofacial development. We have uncovered novel roles for retinoic acid signaling in regulating growth and convergence of the facial prominences in this species that are conserved in mammals. Moreover, perturbing this signaling pathway, at a specific time in development, results in a cleft in the primary palate that closely resembles human median facial clefts. Such facial clefts while rare, are also associated with a number of human syndromes. Moreover, small disturbances in the development of the primary palate have been postulated to be an underlying cause of clefts in the secondary palate. Therefore, our studies of primary palate development could have significant impact on the development of therapeutic interventions and prevention of facial clefts in humans. Our published and preliminary studies have prompted us to form the hypothesis that retinoic acid signaling regulates homeobox genes, epigenetic modulators and cell cycle regulators that converge to ultimately control cell proliferation of the facial tissues that form the primary palate. We test this hypothesis in aims 1 and 2 where we combine modern molecular assays and classical embryology, notably utilizing face transplants and morphometric analyses. Since orofacial development is complex and many factors can contribute birth defects in this region a better understanding of how the primary palate develops is critical. In addition, it is also essential to identify environmental toxins that can influence he endogenous developmental pathways. In the aim 3 we propose to use chemical screens as an unbiased method to find novel mechanisms in primary palate development and to test whether environmental toxins can exacerbate median clefts.