): The splanchnic mesoderm gives rise to visceral musculature and many other integral components of various internal organs. Congenital and sporadic diseases affecting visceral mesoderm derivatives can cause visceral myopathies of the gastrointestinal tract, lymphangioleiomatosis (LAM) of lung smooth muscles, and organogenesis defects, and represent a significant problem for human health. In spite of the major contributions of these tissues to the anatomy and physiology of the body, little is presently known about the regulatory processes that control their development and differentiation. Notably, recent observations in Drosophila have provided important clues to our understanding of visceral mesoderm development in this organism and have produced increasing evidence that at least some of the regulatory processes in the corresponding tissues have been evolutionarily conserved. The studies in Drosophila have shown that visceral mesoderm formation depends on inductive signals, provided by the BMP family member Dpp and mesoderm-intrinsic activities of the NK homeobox genes tinman and bagpipe. Moreover, bagpipe expression is induced in cells that define the visceral mesoderm primordia and genetic studies have identified bagpipe as the first example of a gene that is critically and specifically required for visceral mesoderm and gut muscle formation. The overall goal of the present application is to identify additional genes that participate in successive regulatory steps throughout visceral mesoderm development and to define their functions in visceral mesoderm morphogenesis and gut muscle differentiation. We have recently identified two new genes with prolonged expression in the developing visceral mesoderm, which we believe to play major roles in visceral muscle and gut development downstream of bagpipe. The first, fd65D, encodes a forkhead domain protein while the second, hand, encodes a bHLH transcription factor. We propose herein a detailed analysis of the genetic and molecular functions of these two genes to gain insight into their specific roles in visceral mesoderm development. In addition we propose a simple genetic screen to identify additional regulatory genes in this particular pathway. Altogether, we expect that the regulatory circuits uncovered in these studies will provide new information and important guidance for studies of related pathways in the development of visceral mesodermal tissues.
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