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).

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Intramural Research (Z01)
Project #
1Z01NS002820-12
Application #
6504737
Study Section
(NGU)
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2001
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
Yavatkar, Amarendra S; Lin, Yong; Ross, Jermaine et al. (2008) Rapid detection and curation of conserved DNA via enhanced-BLAT and EvoPrinterHD analysis. BMC Genomics 9:106
Brody, Thomas; Rasband, Wayne; Baler, Kevin et al. (2008) Sequence conservation and combinatorial complexity of Drosophila neural precursor cell enhancers. BMC Genomics 9:371
Brody, Thomas; Yavatkar, Amarendra S; Lin, Yong et al. (2008) Horizontal gene transfers link a human MRSA pathogen to contagious bovine mastitis bacteria. PLoS ONE 3:e3074
Kuzin, Alexander; Kundu, Mukta; Brody, Thomas et al. (2007) The Drosophila nerfin-1 mRNA requires multiple microRNAs to regulate its spatial and temporal translation dynamics in the developing nervous system. Dev Biol 310:35-43
Missirlis, Fanis; Kosmidis, Stylianos; Brody, Tom et al. (2007) Homeostatic mechanisms for iron storage revealed by genetic manipulations and live imaging of Drosophila ferritin. Genetics 177:89-100
Brody, Thomas; Rasband, Wayne; Baler, Kevin et al. (2007) cis-Decoder discovers constellations of conserved DNA sequences shared among tissue-specific enhancers. Genome Biol 8:R75
Kuzin, Alexander; Brody, Thomas; Moore, Adrian W et al. (2005) Nerfin-1 is required for early axon guidance decisions in the developing Drosophila CNS. Dev Biol 277:347-65
Brody, Thomas; Odenwald, Ward F (2005) Regulation of temporal identities during Drosophila neuroblast lineage development. Curr Opin Cell Biol 17:672-5
Odenwald, Ward F; Rasband, Wayne; Kuzin, Alexander et al. (2005) EVOPRINTER, a multigenomic comparative tool for rapid identification of functionally important DNA. Proc Natl Acad Sci U S A 102:14700-5
Odenwald, Ward F (2005) Changing fates on the road to neuronal diversity. Dev Cell 8:133-4

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