First branchial arch syndromes constitute a major biomedical research problem of craniofacial anomalies. Within these syndromes, tooth (e.g. adontia, hypodonita), mandible (e.g.mandibulofacial dysostosis), and tongue (e.g. microglossia) dysmorphogenesis are after described. Interactions between growth factors and their putative downstream target transcription factor genes are implicated in these syndromes. This research proposal is based on the hypothesis that growth factor genes expressed within rhombomere (rl-4) neuroectoderm induce downstream Msx gene expression and represents a developmental code which is transferred via the CNC to the first arch, and there expressed within a metameric organization that specifies tooth, cartilage and tongue ectomesenchyme. Therefore, epithelial-mesenchymal interactions result in specification of each metameric unit (e.g. tooth number, size and shape).
Three Specific Aims are designed to test this hypothesis: (i) To develop an organ culture model suitable to study the fate and cell lineage from rl-4 neuroectoderm to cranial neural crest (CNC)-derived tooth, cartilage and tongue ectomesenchyme during early mouse E7-E9 first arch morphogenesis; (ii) To identify and characterize the fate map and cell lineage for tooth, Meckel's cartilage, and tongue ectomesenchyme, and to correlate the expression of selected growth factors (e.g. PDGFA, TGF-beta2 and EGF and their receptors) with the downstream expression of Msx genes; and (iii) To determine loss of function effects in fate maps and cell lineages for tooth, cartilage and tongue ectomesenchyme cells produced using antisense inhibition or immunoperturbation approaches. Scientific progress made during the previous period of support, as well as recent results from preliminary studies provide the logic and technical feasibility to use molecular genetic techniques to identify and characterize morphoregulatory molecules that control specification for tooth, Meckel's cartilage and tongue formation. When these studies have identified and characterized the pattern and function of growth factor signaling for Msx gene expression to represent the specification of tooth, Meckel's cartilage and tongue ectomesenchyme cell lineages in the mouse animal model system used in these studies, we will direct this molecular and developmental information to investigate the molecular genetics of specific human first branchial arch syndromes.
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