KINASES/EARLY RESPONSE GENES IN OROFACIAL DEVELOPMENT

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A variety of humoral agents, neurotransmitters, growth factors, prostaglandins and ions have been suggested to modulate growth and differentiation of the embryonic mammalian palate. The effects of some of these stimuli in the developing palate are mediated by adenosine-3',5'- monophosphate (cAMP) and its associated kinase, cAMP-dependent protein kinase (cAMP-dPK). The complexity of normal palatogenesis, however, which is dependent upon a myriad of morphological and biochemical processes, clearly dictates that no single key regulatory molecule or pathway exists. Undoubtedly, the extensive alterations in tissue morphology, cellular biochemistry, and cell proliferation that culminate in genesis of the mammalian midface result from the interaction of multiple hormone- and growth factor-activated signalling pathways. Although much attention has been directed towards identifying the biologically relevant external stimuli and the cellular receptors affecting normal palate development, less attention has been focused on the identification and interaction of the multiple signal transduction pathways mediating the effects of these external stimuli. Moreover, no studies, to date, have addressed the nuclear events responsible for transducing the short-term extracellular, transmembrane and cytoplasmic signals into long-term cellular phenotypic alterations associated with normal orofacial development. Accordingly, the current application proposes to investigate the role of the major signal transducer protein kinase C (PKC) in mediating the effects of various palatal hormones and growth factors, as well as examine the role of the 'early response' nuclear oncogene families (fos, myc, jun) in protein kinase-mediated signal transduction during normal growth and differentiation of the mammalian secondary palate. The overall objectives of this application include: 1) determination of the spatio-temporal profile of expression of PKC isozymes and their mRNAs in the developing palate and definition of a functional role for this signal transduction system in embryonic palatal cell growth and glycosaminoglycan synthesis; 2) determination of the spatio-temporal pattern of expression of the 'early response' nuclear oncogenes of the fos, myc and jun families induced by palatal hormones and growth factors, and delineation of a functional role for these genes in embryonic palatal cell proliferation and metabolism; 3) determination of whether the induction of the 'early response' oncogenes in the developing palate is mediated through PKC, and analysis of potential "cross-talk" between the cAMP-dPK and PKC signal transduction pathways; and 4) examination of the effects of ethanol, a teratogen affecting varied orofacial defects, on the expression of the "early response" oncogenes and their respective signal transduction pathways in the developing palate.