The human CNS contains a diversity of neurons and glia that regulate movement, perception, cognition, and overall behavior. Understanding how neuronal diversity is generated is clinically relevant for learning how to manipulate neural stem cells to generate needed cell types on demand, for recognizing the primary defect in neurodegenerative diseases, nervous system cancers, or for understanding behavioral disorders. Drosophila and mammals share a high degree of conservation in the mechanisms regulating neurogenesis, so we are using Drosophila as a model system for understanding how neural diversity is generated. The generation of neuronal and glial diversity requires the production of the appropriate cell types at the right place (spatial patterning) and at the right time (temporal patterning). Disruption of either spatial or temporal patterning can lead to embryonic lethality or birth defects. While the mechanisms regulating spatial pattern formation are well studied, relatively little is known about how neurons and glia are generated at specific times during CNS development. We and others have shown that four transcription factors are sequentially expressed in embryonic neuroblasts (Hunchback, Kruppel, Pdm1/2, and Castor). We have shown that Hunchback and Kruppel are necessary and sufficient for specifying """"""""temporal identity"""""""" in several neuroblast lineages;for example, hunchback mutants lack the first-born neurons whereas extended hunchback expression leads to a reiteration of first-born neurons at the expense of later-born neurons. Major questions that we will address in this grant proposal are: (1) What are the transcriptional targets of Hunchback in the CNS? (2) What is the function of the later genes in the series, Pdm1/2 and Cas? (3) What is the """"""""timer"""""""" that regulates the sequential expression of these four factors? (4) Can we identify additional genes that regulate temporal identity? These questions are relatively difficult to address in mammals, but over the last two decades it has become clear that model organisms such as Drosophila can be used to identify molecules and mechanisms important for mammalian neurogenesis. Thus, we propose to continue our investigation of temporal patterning in the Drosophila CNS, with the goal of providing insight into the mechanisms regulating temporal patterning during mammalian neurogenesis.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Neurogenesis and Cell Fate Study Section (NCF)
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Henken, Deborah B
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University of Oregon
Schools of Arts and Sciences
United States
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Syed, Mubarak Hussain; Mark, Brandon; Doe, Chris Q (2017) Steroid hormone induction of temporal gene expression in Drosophila brain neuroblasts generates neuronal and glial diversity. Elife 6:
Farnsworth, Dylan R; Bayraktar, Omer Ali; Doe, Chris Q (2015) Aging Neural Progenitors Lose Competence to Respond to Mitogenic Notch Signaling. Curr Biol 25:3058-68
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Bayraktar, Omer Ali; Doe, Chris Q (2013) Combinatorial temporal patterning in progenitors expands neural diversity. Nature 498:449-55
Kohwi, Minoree; Doe, Chris Q (2013) Temporal fate specification and neural progenitor competence during development. Nat Rev Neurosci 14:823-38
Kohwi, Minoree; Lupton, Joshua R; Lai, Sen-Lin et al. (2013) Developmentally regulated subnuclear genome reorganization restricts neural progenitor competence in Drosophila. Cell 152:97-108
Manning, Laurina; Heckscher, Ellie S; Purice, Maria D et al. (2012) A resource for manipulating gene expression and analyzing cis-regulatory modules in the Drosophila CNS. Cell Rep 2:1002-13
Carney, Travis D; Miller, Michael R; Robinson, Kristin J et al. (2012) Functional genomics identifies neural stem cell sub-type expression profiles and genes regulating neuroblast homeostasis. Dev Biol 361:137-46
Hirono, Keiko; Margolis, Jonathan S; Posakony, James W et al. (2012) Identification of hunchback cis-regulatory DNA conferring temporal expression in neuroblasts and neurons. Gene Expr Patterns 12:11-7
Lai, Sen-Lin; Miller, Michael R; Robinson, Kristin J et al. (2012) The Snail family member Worniu is continuously required in neuroblasts to prevent Elav-induced premature differentiation. Dev Cell 23:849-57

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