MOLECULAR PATTERNING OF LIMB MORPHOGENESIS

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The adult limb skeleton depends on the proper growth, branching, segmentation, migration and fusion of embryonic cartilages. In this application, we examine the developmental control of a key event in cartilage morphogenesis-the segmentation of a single cartilage into two. Using the chick limb bud as an experimental model, we focus on the control of cartilage segmentation in the embryonic fibula. This element shows a dramatic early segmentation that profoundly affects its final skeletal phenotype. Importantly, this normal segmentation event can be perturbed by experimental manipulation, specifically by placing a barrier between anterior and posterior halves of the pre-cartilaginous limb bud (Hampe, 1960), creating major skeletal defect. To investigate the mechanisms of altered cartilage patterning and the possible causes of limb segmentation defects, we propose to revisit this experimental manipulation at the cellular and molecular level, investigating 1) the role of antero-posterior signaling in the control of limb bud morphogenesis, 2) the importance of cell-cell and cell-matrix interactions during cartilage segmentations, migrations, and fusions, and 3) molecular pathways of cartilage morphogenesis in the early vertebrate limb bud. By comparing normal and abnormal cartilage development at multiple levels, key mechanisms of cartilage morphogenesis will be identified.