The long-term objectives are to understand the mechanisms whereby hormones shape the development of the brain. This proposal uses Drosophila to examine the role of hormones in regulating neurogenesis. Adult-specific clusters of immature neurons are found in the larval CNS of Drosophila and each arises from a single neuronal stem cell (neuroblast, NB). The clusters in the segmental CNS were characterized and mapped using positively marked clones. The proposal uses molecular and genetic approaches to determine how hormone signaling regulates both the neurogenic process itself and the early differentiation of the neurons that are produced.
Specific aims are to: 1) examine the mechanisms that establish and maintain the different identities assumed by sibling neurons born during postembryonic neurogenesis. They focus on the role of Notch signaling and Numb in establishing the two sib identities during postembryonic neurogenesis, and on the transcription factors, engrailed and acj6, in establishing the distinctive identities of sibling neurons. 2) determine the endocrine cues that divide neurons of a hemilineage into subgroups and the role of Broad-Z4 in that process. Hormone dependencies will be established using in vitro approaches. The roles of hormones in terminating stem cell activity will also be examined. 3) describe the time-course of axonal and dendritic arbor growth using EM and 2-photon imaging. The hormonal signals that induce sprouting will be defined and loss-of-function and receptor dominant negative approaches will be used to determine the intrinsic and extrinsic factors that regulate outgrowth. Of special interest is the role of the unliganded receptor complex in suppressing interstitial sprouting as the axon navigates to its initial target. 4) examine the role of the Broad- Z3 transcription factor as a steroid-responsive transcription factor involved in the sprouting response. It uses loss of function approaches to examine the hypothesis that BR-Z3 is involved in defining the character of the outgrowth sites during the start of arbor growth. This proposal uses the molecular genetic tools of Drosophila to determine how hormones establish the duration of neurogenesis and the composition of the cell-types that are produced. Understanding these issues is fundamental to normal brain development and for using stem cells to repair brain disease.
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