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 #
5R37NS040929-13
Application #
8402818
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
2013-01-01
Budget End
2013-12-31
Support Year
13
Fiscal Year
2013
Total Cost
$319,617
Indirect Cost
$112,745
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
Thompson-Peer, Katherine L; DeVault, Laura; Li, Tun et al. (2016) In vivo dendrite regeneration after injury is different from dendrite development. Genes Dev 30:1776-89
Ori-McKenney, Kassandra M; McKenney, Richard J; Huang, Hector H et al. (2016) Phosphorylation of β-Tubulin by the Down Syndrome Kinase, Minibrain/DYRK1a, Regulates Microtubule Dynamics and Dendrite Morphogenesis. Neuron 90:551-63
Meltzer, Shan; Yadav, Smita; Lee, Jiae et al. (2016) Epidermis-Derived Semaphorin Promotes Dendrite Self-Avoidance by Regulating Dendrite-Substrate Adhesion in Drosophila Sensory Neurons. Neuron 89:741-55
Li, Jiefu; Zhang, Wei; Guo, Zhenhao et al. (2016) A Defensive Kicking Behavior in Response to Mechanical Stimuli Mediated by Drosophila Wing Margin Bristles. J Neurosci 36:11275-11282
Guo, Yanmeng; Wang, Yuping; Zhang, Wei et al. (2016) Transmembrane channel-like (tmc) gene regulates Drosophila larval locomotion. Proc Natl Acad Sci U S A 113:7243-8
Soba, Peter; Han, Chun; Zheng, Yi et al. (2015) The Ret receptor regulates sensory neuron dendrite growth and integrin mediated adhesion. Elife 4:
Zhang, Wei; Cheng, Li E; Kittelmann, Maike et al. (2015) Ankyrin Repeats Convey Force to Gate the NOMPC Mechanotransduction Channel. Cell 162:1391-403
Song, Yuanquan; Sretavan, David; Salegio, Ernesto A et al. (2015) Regulation of axon regeneration by the RNA repair and splicing pathway. Nat Neurosci 18:817-25
Huang, Xi; He, Ye; Dubuc, Adrian M et al. (2015) EAG2 potassium channel with evolutionarily conserved function as a brain tumor target. Nat Neurosci 18:1236-46
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

Showing the most recent 10 out of 36 publications