Members of the basic-Helix-Loop-Helix (bHLH) class of transcription factors have been shown to regulate cell growth and differentiation of a variety of cell types. We have recently cloned two novel bHLH proteins, referred to as Meso1 and -2, which are nearly identical within their bHLH regions but are divergent in their amino- and carboxyl-termini. During mouse embryogenesis, Meso1 is expressed in the paraxial mesoderm prior to somite formation, in the newly formed somites, and in limb buds. later in development, Meso1 expression becomes restricted to skeletal muscle and heart. Meso2 is first expressed within the sclerotomal region of the somites and is subsequently detected at high levels within mesenchymal precursors of the ribs and vertebrae and in condensing cartilage of the nose and face. The sequential pattern of expression of Meso1 and -2 in mesodermal cell lineages is reminiscent of the expression patterns of the MyoD and Achaete scute families of bHLH proteins, which regulate myogenesis and neurogenesis, respectively, and suggests that Meso1 and -2 may constitute a regulatory network that specifies cell fate in mesodermal cell lineages. The goals of this proposal are 1) to define the functions of Meso1 and -2 using a variety of gain-of-function assays in vivo and in vitro, 2) to identify extracellular signals that activate Meso1 and -2 expression during embryogenesis, 3) to define the cis- and trans- regulatory systems that control the Meso1 and -2 genes during embryogenesis, and 4) to assess the consequences of inactivating the Meso1 and -2 genes on embryonic development. These studies will further our understanding of the mechanisms involved in establishment of the vertebrate body plan and should reveal fundamental mechanisms for cell fate specification in the embryo.
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