The objective of this program is to identify and functionally characterize transcription factor regulatory networks controlling cell-identity decisions in the developing central nervous system (CNS). During CNS development, stem cells undergo multiple rounds of asymmetric cell divisions, producing either neuronal or glial progenitor cells with each division. Underpinning the formation of stem cell lineages are integrated regulatory networks that establish distinct cellular identities and, ultimately, create unique neuronal/glial subtypes within their lineages. Although much is known about early developmental decision leading to the formation of neural stem cells, little is understood about subsequent cell fate decisions that generate the unique functional identities of neurons or glia. The identification and functional characterization of the molecules and pathways/circuits underlying these cell fate decisions remains a central goal of neurobiology. We have discovered that in the developing Drosophila CNS most, if not all, stem cells transition through a series of synchronized gene expression programs during their asymmetric divisions. These temporal windows of gene expression are marked by the sequential production of different transcription factors that in turn help establish unique neural cell types. Our studies have revealed that the temporal domains are part of a global CNS regulatory network that coordinates cell fate-determining events. In the past year, we have discovered that when cultured in isolation, Drosophila stem cells maintain the correct temporal shifts in transcription factor gene expression. This cellular independence demonstrates that once neural lineage development is initiated no additional signaling cues between stem cells or adjacent tissues are required to trigger this cascade of regulatory gene expression. In addition, our work on the characterization of novel genes identified from a differential cDNA in situ hybridization screen of Drosophila genes expressed in the embryonic head has resulted in new insights into the regulatory genes controlling CNS development. In particular, analysis of the novel genes, Nerfin-1 and Nerfin-2, reveal that they belong to a highly conserved Zn-finger transcription factor gene subfamily with human and nematode cognates. Nerfin-1 is expressed in neural stem cells while Nerfin-2 is expressed in a subset of brain neurons. Functional analysis of nerfin-1 has revealed that its encoded protein is required for the proper expression of both neuronal and glial identity genes in most, if not all, CNS lineages. Understanding neural cell-identity decisions will ultimately have significant implications for identifying and treating developmental defects. Given that many, if not most, of the genes employed to construct a functioning nervous system are highly conserved among metazoans, deciphering the regulatory logic of Drosophila CNS development will most certainly aid in our understanding of human development. Additional information and publications describing this work can be obtained at our web site (http://intra.ninds.nih.gov/investigators.asp).
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