For a nervous system to be properly wired up, the axons have to be guided toward the correct targets and the dendrites need to have the correct branching pattern and structural specialization. Despite considerable progresses that have been made recently, we still know relatively little about the molecular mechanisms that control dendrite development as compared to those controlling axon guidance. We hypothesize that a systematic screen for dendrite mutants in a model system is likely to provide a comprehensive means of identifying those molecular mechanisms. Once the molecular basis is characterized, it will be possible to test for its general applicability in other animals. For this purpose, we have developed the multiple dendritic (MD) neurons of the Drosophila peripheral nervous system (PNS) as a model system. We have been using this model system to perform a genetic dissection of dendrite development by identifying, cloning and studying genes of interest in order to uncover the "core programs" that control dendrite morphogenesis. Our ongoing study has begun to yield important insights about the molecular basis of dendrite development in Drosophila. Our studies have helped to formulate important questions that have only begun to be addressed. For this proposal, we will focus on three areas: the differential regulation of dendrite and axon growth;the molecular mechanisms that control dendritic self-avoidance and tiling and the molecular machinery used to maintain dendritic arbors. Given the striking conservation of many molecular mechanisms that control various developmental processes including axon guidance, it is highly likely that many of the molecular mechanisms controlling dendrite development are conserved between Drosophila and mammals. Indeed, we have already had considerable success in our ongoing efforts to extend our findings from Drosophila to mammalian brain. Since dendrite defects have been implicated in certain human mental disorders such as autism, this work will contribute to the understanding and eventual treatment of human neurological diseases many of which have pathology in dendrites.

Public Health Relevance

This project aims to elucidate the molecular mechanisms that control dendrite development by using Drosophila sensory neurons as a model system. Given there is already strong evidence that many molecular mechanisms that control dendrite development are evolutionarily conserved, this work is likely to contribute to the understanding and eventual treatment of human neurological disorders, many of which have pathology in dendrites.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37NS040929-12
Application #
8209120
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Mamounas, Laura
Project Start
2001-01-18
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
12
Fiscal Year
2012
Total Cost
$331,209
Indirect Cost
$116,834
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
Yuan, Quan; Song, Yuanquan; Yang, Chung-Hui et al. (2014) Female contact modulates male aggression via a sexually dimorphic GABAergic circuit in Drosophila. Nat Neurosci 17:81-8
Rumpf, Sebastian; Bagley, Joshua A; Thompson-Peer, Katherine L et al. (2014) Drosophila Valosin-Containing Protein is required for dendrite pruning through a regulatory role in mRNA metabolism. Proc Natl Acad Sci U S A 111:7331-6
Zhang, Wei; Yan, Zhiqiang; Li, Bingxue et al. (2014) Identification of motor neurons and a mechanosensitive sensory neuron in the defecation circuitry of Drosophila larvae. Elife 3:
Han, Chun; Song, Yuanquan; Xiao, Hui et al. (2014) Epidermal cells are the primary phagocytes in the fragmentation and clearance of degenerating dendrites in Drosophila. Neuron 81:544-60
Parrish, Jay Z; Kim, Charles C; Tang, Lamont et al. (2014) Kr├╝ppel mediates the selective rebalancing of ion channel expression. Neuron 82:537-44
Bagley, Joshua A; Yan, Zhiqiang; Zhang, Wei et al. (2014) Double-bromo and extraterminal (BET) domain proteins regulate dendrite morphology and mechanosensory function. Genes Dev 28:1940-56
Gorczyca, David A; Younger, Susan; Meltzer, Shan et al. (2014) Identification of Ppk26, a DEG/ENaC Channel Functioning with Ppk1 in a Mutually Dependent Manner to Guide Locomotion Behavior in Drosophila. Cell Rep 9:1446-58
Huang, Xi; Jan, Lily Yeh (2014) Targeting potassium channels in cancer. J Cell Biol 206:151-62
Yan, Zhiqiang; Zhang, Wei; He, Ye et al. (2013) Drosophila NOMPC is a mechanotransduction channel subunit for gentle-touch sensation. Nature 493:221-5
Zhang, Wei; Yan, Zhiqiang; Jan, Lily Yeh et al. (2013) Sound response mediated by the TRP channels NOMPC, NANCHUNG, and INACTIVE in chordotonal organs of Drosophila larvae. Proc Natl Acad Sci U S A 110:13612-7

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