Axon branching is a key step in developing neural circuits that are critical to human behaviors. During embryonic development, formation of axonal branches is high regulated in time and space, and disruption of normal control can cause synaptic defects associated with many neurological and psychiatric disorders. Although molecular mechanisms have begun to be identified in the past decade, the precise temporal and spatial control of axon branching is poorly understood. The central projection of the sensory neurons in the dorsal root ganglion develops stereotypic branches that are found in many vertebrates. They include axon bifurcation at the dorsal spinal cord that relays somatosensory information such as pain and touch to the brain, and collateral branches that invade the white matter and form local reflex arcs. Formation of these branches is precisely regulated during development, making them excellent model to understand molecular and cellular mechanisms of axon branching. Following our recent identification of extracellular cues for bifurcation and intrinsic determinants for collateral formation, the proposed study will use both in vitro cultures and mouse mutants to investigate the mechanisms underlying the formation of both structures. Specifically, we will combine molecular, genetic, biochemical, and cell biological approaches to address three key questions: 1) How do extracellular cues cooperate and regulate the intracellular machineries to ensure bifurcation happens once and only once at a defined location? 2) How does a cytoskeleton protein MAP7 serve as a signaling center to regulate sensory collateral formation? 3) How does the expression of transcriptional co-factors Ldb1/2 contribute to the developmental time control for collateral formation? Answers to these questions will help understand the mechanisms governing the temporal and spatial regulation of branching that is critical to sensory circuit development. Given the wide expression of these molecules and the frequent appearance of the two branching processes, our proposed studies of this evolutionarily conserved cell model will fill in a major gap in our study of axon branching We also expect that the knowledge obtained here can be translated to understanding other brain circuits. Thus the proposed studies are highly relevant to the mission of investigating brain functions and disorders.

Public Health Relevance

The goal of the proposed research is to understand both extracellular and intrinsic mechanisms underlying the spatial and temporal control of axon branching during development. It focuses on two stereotypic branched structures of sensory axons in the spinal cord. Results from the proposed study will not only provide a better understanding of neural circuit development, but also shed lights on the etiology of developmental brain disorders associated with abnormal branching regulation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS062047-06
Application #
8761846
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Riddle, Robert D
Project Start
2008-04-01
Project End
2019-05-31
Budget Start
2014-09-20
Budget End
2015-05-31
Support Year
6
Fiscal Year
2014
Total Cost
$339,427
Indirect Cost
$120,677
Name
Thomas Jefferson University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Gibson, Daniel A; Tymanskyj, Stephen; Yuan, Rachel C et al. (2014) Dendrite self-avoidance requires cell-autonomous slit/robo signaling in cerebellar purkinje cells. Neuron 81:1040-56
Domyan, Eric Thomas; Branchfield, Kelsey; Gibson, Daniel A et al. (2013) Roundabout receptors are critical for foregut separation from the body wall. Dev Cell 24:52-63
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
Xia, Caihong; Nguyen, Minh; Garrison, Amy K et al. (2013) CNP/cGMP signaling regulates axon branching and growth by modulating microtubule polymerization. Dev Neurobiol 73:673-87
Gibson, Daniel A; Ma, Le (2011) Developmental regulation of axon branching in the vertebrate nervous system. Development 138:183-95
Bai, Ge; Chivatakarn, Onanong; Bonanomi, Dario et al. (2011) Presenilin-dependent receptor processing is required for axon guidance. Cell 144:106-18
Zhao, Zhen; Wang, Zheng; Gu, Ying et al. (2009) Regulate axon branching by the cyclic GMP pathway via inhibition of glycogen synthase kinase 3 in dorsal root ganglion sensory neurons. J Neurosci 29:1350-60
Zhao, Zhen; Ma, Le (2009) Regulation of axonal development by natriuretic peptide hormones. Proc Natl Acad Sci U S A 106:18016-21