Normal human cognition relies on functional neuronal circuits that are assembled during development. Neuronal polarity and morphology are integral to forming proper neuronal connections, although the question of how neuronal polarity and morphology are established in vivo remains largely unanswered. Using the fruit fly as a model system, the aims of this proposal are to (1) conduct an in vivo forward genetic screen to uncover novel neuronal polarity and morphology regulators, (2) characterize a polarity mutant identified in this screen and (3) identify the mammalian homologs of fly neuronal polarity/morphology genes and analyze their function in cultured mammalian neurons. The genetic screen uses a GFP construct to visualize a class of multipolar neurons in living fly embryos and larvae, facilitating the screening process. The screen has uncovered a polarity mutant, which will be characterized by first identifying the gene corresponding to the mutation and then determining the mechanism by which it functions. Lastly, to better understand the conserved mechanisms regulating neuronal polarity and morphology, genes identified in the genetic screen will be analyzed in cultured mammalian neurons. Specifically, mammalian homologs of the fly mutants will be identified and their role in neuronal polarity/morphology will be assessed using cultured hippocampal neurons. In conclusion, the goal of this proposal is identify novel regulators of neuronal polarity and morphology and to characterize their function in both flies and cultured mammalian neurons. Therefore, the results of these studies will likely shed light on conserved mechanisms regulating neuronal polarity and morphology. Public Health Relevance: Multiple human developmental disorders, including lissencephaly and mental retardation, are associated with abnormal neuronal polarity and/or morphology. This goal of this proposal is understand how neuronal polarity and morphology are established in vivo, which will contribute to our understanding of how neural circuits assemble. Such knowledge can be applied to treating human disorders. ? ?

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32HD053199-01A1
Application #
7275026
Study Section
Special Emphasis Panel (ZRG1-F03A-M (20))
Program Officer
Henken, Deborah B
Project Start
2007-07-01
Project End
2010-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
1
Fiscal Year
2007
Total Cost
$49,646
Indirect Cost
Name
University of California San Francisco
Department
Physiology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Zhu, Sijun; Wildonger, Jill; Barshow, Suzanne et al. (2012) The bHLH repressor Deadpan regulates the self-renewal and specification of Drosophila larval neural stem cells independently of Notch. PLoS One 7:e46724
Wildonger, Jill; Jan, Lily Yeh; Jan, Yuh Nung (2008) The Tsc1-Tsc2 complex influences neuronal polarity by modulating TORC1 activity and SAD levels. Genes Dev 22:2447-53
Zheng, Yi; Wildonger, Jill; Ye, Bing et al. (2008) Dynein is required for polarized dendritic transport and uniform microtubule orientation in axons. Nat Cell Biol 10:1172-80