The broad goal of this research proposal is to understand the molecular and cellular basis of signaling mechanisms underlying mesoderm induction in the vertebrate embryo. In Xenopus, mesoderm induction involves at least two intracellular signaling pathways, downstream of the FGF and TGF-beta receptors. Overexpression of components of either pathway causes ectopic formation of mesoderm, while interruption of signaling through either pathway inhibits mesoderm formation in vivo. The two signaling pathways may interact, as FGF signaling is required for TGF-beta pathway function; it has been proposed that FGF signaling is involved in the competence of early tissue to form mesoderm in response to a TGF-beta inducing cue. Laloo, a novel member of the Src-related gene family, plays a critical role in FGF-mediated mesoderm induction. This application focuses on the FGF-Laloo pathway: the proposed studies aim to characterize the molecular interactions underlying signaling by Laloo, using a combination of embryological and biochemical approaches. Experiments are designed to 1) elucidate the mechanisms by which the FGF receptor regulates the activity of Laloo, 2) determine the specificity of signaling by the Src-like kinases, and 3) characterize the role of extracellular matrix components in Laloo activation. These experiments should provide a detailed understanding of the mechanisms by which Laloo mediates mesoderm induction by FGF, and will extend, considerably, the understanding of Src kinase function in this fundamental step in vertebrate development. These experiments will also lay the groundwork for future studies designed to explore the means by which this pathway and others coordinate the range, timing, and extent of mesoderm induction during vertebrate embryogenesis.
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