9722863 SCHULZ Proteins that act as transcription factors, which control the expression of one or more other genes, are very important in determining how different cell types take on different characteristics during development. One small family of transcription factors, called the myocyte enhancer factor-2 (MEF2) family, is expressed in muscle cells and is highly conserved at the genetic level across a wide range of animals. The analysis of MEF2 function has been greatly facilitated by the study of D-mef2, the single mef2 gene of the laboratory fruitfly, Drosophila melanogaster. Embryos lacking a normal D-mef2 gene fail to form normal muscles. The gene controls differentiation in all muscle cell types, and its absence results in lethality during embryonic development. Mef2 genes are also expressed in non-muscle cell types. For example, the mouse and human versions of this genes are expressed in neurons of the brain. Throughout development, mef2 gene expression appears to follow gradients of neuronal maturation and the initiation of neuronal cell differentiation. D-mef2 is also expressed in the Drosophila central nervous system in Kenyon cells, which are the intrinsic neurons of the mushroom bodies of the brain. Very little is known about the development of these neural centers, which are required for associative learning in flies. Given the mushroom body-enriched expression of D-mef2, and the known function of the gene in muscle differentiation, it is likely that this transcription factor also functions in this neuronal cell. Because of the expected difficulties in elucidating the functions of the vertebrate genes in the mouse or human brains, studies conducted using the Drosophila model system should yield the first insights into the functions of a MEF2 family member in complex neural developmental processes. The overall goal of this project is to build upon previous genetic and molecular discoveries to investigate the function of the D-mef2 gene in neurons. The specific aims a re to characterize the regulatory factors controlling D-mef2 expression in Kenyon neurons and to determine the function of D-mef2 in these cells. Since the genetic programs controlling brain development in flies and higher eukaryotes are believed to be highly conserved, these experiments should be important to the understanding of neuron differentiation during central nervous system development.
