How the correct cell-types develop at the right time and place in an organism remains a central and enduring question in developmental biology. In no other tissue are the processes that generate and pattern cell-types taken to such extremes as in the developing CNS. Our research uses the Drosophila CNS as a model system to explore the genetic and molecular basis of cell-type diversity. We focus on the developmental mechanisms that act during post-embryonic neurogenesis to generate the neurons of the adult CNS. Post-embyronic neurogenesis commences during the first larval stage when neuroblasts reactivate division in response to the presence of dietary amino acids. Most post-embryonic neurons, however, are born during a rapid, prolonged burst of neuroblast proliferation that starts in the early third larval stage and that foreshadows, and continues past, the onset of metamorphosis. Between the time when neuroblast's reactivate proliferation and the onset of metamorphosis, larvae undergo a massive increase in size, and emerging studies suggest complex regulatory networks couple post-embryonic neurogenesis to physiology. However, both the systemic and intrinsic mechanisms that control post-embryonic neurogenesis are poorly understood. At present, studies on post-embryonic neurogenesis are limited by the inability to identify most adult neuroblast lineages based solely on gene expression and the paucity of genes known to regulate this process. We have identified ten transcription factors, the expression of which label most adult neuroblast lineages, providing the molecular tools to build the descriptive basis for detailed studies on post-embryonic neurogenesis. The overlapping expression profiles of these genes suggest they act in combination to specify the identity of individual neuronal hemilineages. And, via the wedding of forward genetic screens to whole genome sequencing methods, we have begun to identify the genes that control distinct steps of post-embryonic neurogenesis, including a putative GPCR that may couple the action of juvenile hormone to neuroblast division. Our proposed studies seek to transform these findings into an ever-clearer picture of the complex and coordinated regulatory networks that control post-embryonic neurogenesis.
Our specific aims are to: ? Generate a gene expression map of all adult thoracic neuroblast lineages ? Test if a combinatorial code of transcription factors specifies the identity of neuronal hemilineages ? Identify genes that control post-embryonic neurogenesis via genetic screens and whole genome sequencing ? Characterize the mechanisms through which a GPCR governs post-embryonic neurogenesis
The proposed project aims to investigate the genetic and molecular control of post-embryonic neurogenesis. The study integrates approaches ranging from classical genetical and embryological methods to whole genome sequencing methods to establish the descriptive and genetic foundation required to clarify the genetic and molecular basis of post-embryonic neurogenesis, and to characterize the function of a putative GPCR that may couple physiological status to neurogenesis.
|Arthur, Laura L; Chung, Joyce J; Jankirama, Preetam et al. (2017) Rapid generation of hypomorphic mutations. Nat Commun 8:14112|
|Skeath, James B; Wilson, Beth A; Romero, Selena E et al. (2017) The extracellular metalloprotease AdamTS-A anchors neural lineages in place within and preserves the architecture of the central nervous system. Development 144:3102-3113|
|Snee, Mark J; Wilson, William C; Zhu, Yi et al. (2016) Collaborative Control of Cell Cycle Progression by the RNA Exonuclease Dis3 and Ras Is Conserved Across Species. Genetics 203:749-62|
|He, Zhiwen; O'Neal, Julie; Wilson, William C et al. (2016) Deletion of Rb1 induces both hyperproliferation and cell death in murine germinal center B cells. Exp Hematol 44:161-5.e4|
|Lacin, Haluk; Zhu, Yi; Wilson, Beth A et al. (2014) Transcription factor expression uniquely identifies most postembryonic neuronal lineages in the Drosophila thoracic central nervous system. Development 141:1011-21|
|Drake, Melanie; Furuta, Tokiko; Suen, Kin Man et al. (2014) A requirement for ERK-dependent Dicer phosphorylation in coordinating oocyte-to-embryo transition in C. elegans. Dev Cell 31:614-28|
|Lacin, Haluk; Rusch, Jannette; Yeh, Raymond T et al. (2014) Genome-wide identification of Drosophila Hb9 targets reveals a pivotal role in directing the transcriptome within eight neuronal lineages, including activation of nitric oxide synthase and Fd59a/Fox-D. Dev Biol 388:117-33|
|Yashiro, Hanako; Loza, Andrew J; Skeath, James B et al. (2014) Rho1 regulates adherens junction remodeling by promoting recycling endosome formation through activation of myosin II. Mol Biol Cell 25:2956-69|
|Guss, Kirsten A; Benson, Michael; Gubitosi, Nicholas et al. (2013) Expression and function of scalloped during Drosophila development. Dev Dyn 242:874-85|
|Valakh, Vera; Walker, Lauren J; Skeath, James B et al. (2013) Loss of the spectraplakin short stop activates the DLK injury response pathway in Drosophila. J Neurosci 33:17863-73|
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