The goal of this is to elucidate the functions of the extracellular matrix and cell surface macromolecule hyaluronan (HA) in vertebrate limb morphogenesis. HA is a huge linear glycosaminoglycan which occupies an extensive molecular domain and has a pronounced hydration capacity. HA promotes the migration and proliferation of cells in a variety of model systems, and the binding of HA to its cell surface receptors including CD44 can also activate intracellular signaling. HA has recently been implicated as a costimulator of the EGFR/ErbB signaling network, which is a signaling pathway involved limb morphogenesis and patterning. The distal subapical mesenchymal cells of the developing limb bud, which are undergoing proliferation and patterning in response to the apical ectodermal ridge (AER) and other signaling centers, produce high amounts of HA which forms an expansive hydrated extracellular matrix between the cells. Thus, the cell and tissue interactions controlling the outgrowth and patterning of the limb occur in an environment rich in extracellular and pericellular HA. Based on its role in stimulating proliferation, migration, and intracellular signaling in many other systems, the hypothesis that HA facilitates the proliferation and directed migration of the subapical mesenchymal cells in response to the AER will be investigated, as will the hypothesis that HA modulates one or more of the signaling pathways particularly the EGFR/ErbB signaling network that regulates limb patterning events in the subapical mesoderm. As the mesenchymal cells in the central core of the limb bud become located outside of the range of AER signaling, HA production declines to low levels and extracellular HA is removed. The hypothesis that this downregulation of HA synthesis and removal of extracellular HA is necessary for the cells to form the precartilage condensations that trigger chondrogenic differentiation will be investigated. HA is also synthesized in relatively high amounts by the AER. The hypothesis that HA secreted by the AER may play an important role in facilitating the AER-subridge mesoderm interactions that result in directed limb outgrowth will be investigated.
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