Molecular Regulation of Embryonic Limb and Facial Cartilage Differentiation

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Most bones of the adult body are generated from cartilage tissue templates that are formed during the period of embryonic development. Therefore, elucidating the mechanisms that govern cartilage formation within the embryo is crucial for understanding normal skeletal development. My research program is broadly aimed at clarifying the molecular pathways that control cartilage cell (chondrocyte) differentiation in the limbs and individual facial regions of the vertebrate embryo. Our research is currently focused on identifying the roles that various protein kinase enzymes play in relaying growth regulatory signals from the surface of chondrocyte progenitor cells to crucial target genes within the nucleus. We have recently shown that the cytoplasmic ERK1/2 protein kinase system relays signals from Fibroblast Growth Factor (FGFs) acting on the chondrocyte cell surface. Intriguingly, both FGFs and ERK1/2 have location-dependent effects, stimulating cartilage formation in cells from the mandibular region of the face, but inhibiting cartilage differentiation in cells from the developing limbs and the frontonasal region of the face. In the present project, we will test the hypothesis that the differential responses of mandibular, frontonasal, and limb cell populations to FGF and ERK1/2 signals are the result of differences in their expression of nuclear proteins of the PEA3 family (i.e., Er81, Pea3 and Erm transcription factors). In addition, we will investigate the role of a distinct protein kinase system, the ERK5 pathway, in embryonic cartilage formation. Finally, we will employ an innovative "kinome profiling" proteomic technique to initiate a comprehensive analysis of the multiple protein kinase systems interactions that regulate chondrogenesis. These studies will uncover novel molecular mechanisms controlling normal skeletal development in the limb and facial areas of the embryo, and may provide insight into the causes of some congenital bone malformations. In addition, our findings may suggest avenues for the refinement of cartilage tissue engineering strategies aimed at fabricating replacement tissue for injured joints.