Directed neuronal navigation, including both cell body migration and growth cone path-finding, is a pre- requisite for the establishment of the precisely wired neural network and is essential for the proper function of the brain. Accumulating evidence suggests that growth cone navigation and neuronal cell navigation during early development share many similar features, including responses to a similar set of guidance cues, activation of specific intracellular signaling cascades and cytoskeletal changes for directed movements. For example, netrin-1, an evolutionally conserved long-range growth cone guidance cue essential for neural circuit formation during development, also directs cell migration of cortical neurons and olfactory neurons. Ca2+ signaling has emerged as a central player in mediating growth cone and cellular responses to many guidance cues, including netrin-1. The spatial and temporal regulation of Ca2+ signaling underlying directed neuronal navigation, however, is not well understood. While neural network formation occurs predominantly during the prenatal and early postnatal periods, new neurons are continuously generated from neural progenitors and integrated into the existing neural network in discrete regions of adult mammalian brain, including the subventricular zone (SVZ) of the lateral ventricle and the subgranular zone (SGZ) of the hippocampus. Neurodevelopment in the adult brain recapitulates the major neural developmental milestones, from proliferation and fate specification of neural progenitors, to neuronal morphogenesis, cell migration, axon and dendritic guidance, and synapse formation by neuronal progeny. Because adult neurogenesis occurs in a significantly different environment from embryonic neurogenesis, whether the molecular mechanisms underlying neural development are conserved is not clear. Our long-term goal is to understand the molecular and cellular mechanisms that determine the motility and directionality of developing neurons in response to guidance cues and to develop therapeutic strategies to promote regeneration after injury or diseases of the human central nervous system (CNS). In the current project, we aim to understand the role of Ca2+ signaling in regulating neuronal navigation during early neural development and in the adult brain with the central hypothesis that TRPC, STIM1 and Orai proteins co-operate to set the basal and induced Ca2+ levels for directed motility of growth cones and neurons, using a combination of in vitro growth cone turning assay, immunocytochemistry, multi-photon confocal microscopy and electrophysiology. Our study will provide important information on the molecular mechanisms underlying neuronal navigation and may lead to novel insights as to whether neuronal navigation processes are similarly or differentially regulated in the mature brain, which is important for developing strategies in promoting regeneration.

Public Health Relevance

The project aims at understanding the functional roles of STIM1, TRPC and Orai proteins in regulating the calcium changes for directed growth cone guidance and neuronal cell migration during embryonic development and in the adult brain. Findings from these studies may lead to novel strategies to functionally replace damaged or lost neurons and to promote endogenous repair after injury or degenerative neurological disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS048271-08
Application #
8298480
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Riddle, Robert D
Project Start
2004-03-01
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
8
Fiscal Year
2012
Total Cost
$351,575
Indirect Cost
$137,200
Name
Johns Hopkins University
Department
Neurology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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