The objective of this program is to identify and functionally characterize neurogenic genes that are required for CNS development. Given the high conservation in basic developmental mechanisms used by all metazoans, we have focused our efforts on the study of CNS development in the fruit fly (Drosophila melanogaster), where the genetic information required for these events is accessible. Using classical genetic, molecular biology and transgenic techniques, we have continued to study the function of genes expressed during neuroblast lineage differentiation. Thus far, our study of castor (cas), a novel Zinc finger gene required for proper CNS neuroblast development, has revealed that it encodes a nuclear located, sequence-specific DNA- binding protein whose expression is restricted to late forming CNS neuronal precursor sublineages. We hypothesize that the Cas protein functions as a transcription factor required for correct regulation of genes in these cells. Our recent studies have shown that cas controls cell fate decisions by regulating the expression of all known POU genes during CNS development. POU transcription factors establish neuronal identities in metazoans, yet little is known about the regulatory networks controlling their expression. Cas shares DNA-binding specificity with another pdm repressor, the gap-segmentation gene regulator Hunchback (Hb). Our studies reveal for the first time that all CNS ganglia contain sequentially layered neuroblast progeny subpopulations that can be distinguished by their expression of either Hb, Pdm-1 or Cas. By ensuring correct POU gene expression boundaries, hb and cas maintain temporal subdivisions in the cell- identity circuitry controlling CNS cellular diversity... Phenotypic analysis of loss of function mutations in hb, pdm or cas, by us and others, has shown each of these regulators carryout essential but distinct roles during NB lineage development. Due to the shared expression of these transcription factors, cells within a given expression domain may have overlapping repertoires of downstream target gene expression. To test this hypothesis, we are preparing cDNAs from isolated Hb, Pdm or Cas expressing neuroblasts. Using differential screening and in situ hybridization techniques we will search for genes whose expression is restricted to specific layers. By identifying additional target genes whose expression is restricted, we hope to not only expand our understanding of this regulatory network but also to connect these genetic circuits to genes those encoded proteins impart distinct neuronal phenotypes. - Developmental Neurobiology, Drosophila CNS Neuroblast Stem Cells

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Intramural Research (Z01)
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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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