Axon branching allows a neuron to communicate with multiple partners and helps establish morphologically and functionally distinct neural networks. To ensure proper synaptic connections, branching is tightly regulated by signaling pathways that allow environmental cues to instruct axons when and where to make branches. The long term goal of the proposed research is to investigate the molecular and cellular basis of this regulation, understand how it contributes to the initial development and the subsequent plastic rearrangement of synaptic connections, and provide insights into how to regenerate new branches and functional connections after injury. Using the development of stereotypic axonal branches of rodent sensory neurons from the dorsal root ganglion and trigeminal ganglion as models, we have identified an extracellular signaling pathway involving the secreted molecule Slit in promoting axon branching. In addition, our preliminary studies have demonstrated that the cGMP pathway provides an intracellular signaling mechanism for branching regulation. Using primary sensory neuron cultures and knockout mice, we propose the following three aims to further characterize the role of cGMP signaling: 1) use in vivo analysis to establish cGMP signaling as a general signaling mechanism in regulating the development of diverse yet stereotypic sensory axon branches;2) identify the downstream signaling mechanism mediating the cGMP activity in sensory axon branching;3) determine the cellular mechanism underlying the spatial and temporal control of axon branching.
These aims should help establish a distinct signaling pathway in regulating axon branching and fill in a major gap in our understanding of an important process in making synaptic connections. In addition, since loss of synaptic stability is the hallmark of many neurological disorders, our study of this fundamental process should provide new insights into the etiology of these diseases.

Public Health Relevance

The goal of the proposed research is to investigate the molecular and cellular basis of axon branching, an important process in making synaptic connections and establishing neural networks. We will use a combination of molecular, cellular and genetic approaches to characterize key molecular pathways and identify the signaling mechanisms underlying the regulation of axon branching. The knowledge obtained from this study will not only help understand brain development, but also provide new insights into the molecular basis of many neurological disorders as well as how to promote nerve regeneration after stroke and injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS062047-05
Application #
8470721
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Riddle, Robert D
Project Start
2009-07-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2013
Total Cost
$335,133
Indirect Cost
$128,261
Name
University of Southern California
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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Wang, Sheng-zhi; Ibrahim, Leena A; Kim, Young J et al. (2013) Slit/Robo signaling mediates spatial positioning of spiral ganglion neurons during development of cochlear innervation. J Neurosci 33:12242-54
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