Although adult neurogenesis provides new neurons to some regions of the central nervous system, whether this also occurs in the peripheral nervous system is not known. Our recent in vivo studies in zebrafish larvae suggest that another mechanism might serve as a source of new neurons for the peripheral nervous system. We have found that a subset of differentiated dorsal root ganglion neurons to migrate new ventral locations and acquire new morphologies and molecular properties. The novel characteristics are all indicative of adoption of a new identity as a sympathetic ganglion neuron. Importantly, dorsal root ganglion neurons can acquire sympathetic ganglion neuron-like properties in wild type larvae under control conditions. However, sensory deprivation and blockade of a specific sodium channel, Nav1.6a, increases the number of dorsal root ganglion neurons that acquire a new identity, i.e., transdifferentiate. Even though Nav1.6a is normally expressed in several neurons, the channel's activity is required in only one cell type for maintenance of dorsal root ganglion identity. Interestingly, that cell type is not the dorsal root ganglion neuron but rather n earlier appearing sensory neuron, known as the Rohon-Beard cell. Our previous work has also shown that the neurotrophin BDNF mediates that Nav1.6a-activity-dependent signal. Recently, we have found that differentiated dorsal root ganglion neurons migrate to yet other locations besides the sympathetic ganglion, raising the possibility that migratory dorsal root ganglion neurons might assume other fates than that of the sympathetic ganglion neuron. Here we propose three Specific Aims that will provide important information about the underlying mechanisms involved in the relevant BDNF- dependent signaling.
In Aim 1, we identify the cell types that secrete and respond to the relevant BDNF.
In Aim 2, we determine the full range of cellular identities that migratory dorsal root ganglion neurons may adopt.
Aim 3 experiments identify gene expression changes that underlie BDNF's regulation of the migratory phenotype of differentiated DRG neurons. The results will provide information that could lead to alternative strategies for treatment of neurodegenerative conditions.

Public Health Relevance

As human life span increases, so does the incidence and burden of neurological disease involving neurodegenerative conditions. Current strategies to treat such conditions focus on stem cells and cell transplantation. Here, we identify mechanism that underlying the recently discovered ability of a differentiated neuron to adopt a new identity (i.e., transdifferentiate) in vivo and obtain information that could lead to alternative strategiesfor treatment of neurodegenerative conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS086839-01
Application #
8670308
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Riddle, Robert D
Project Start
2014-02-01
Project End
2019-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
1
Fiscal Year
2014
Total Cost
$335,682
Indirect Cost
$116,932
Name
University of Colorado Denver
Department
Physiology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045