The specific regulatory pathways regulating adult neurogenesis and the behavior of neural stem cells are poorly understood. Radial glial stem cells in the vertebrate brain can continuously produce neurons during homeostasis and regenerate lost cells following injury. Yet the molecular mechanisms underlying neural stem cell regulation are poorly understood. Our laboratory has discovered that Wnt signaling regulates neurogenesis in the post-embryonic zebrafish hypothalamus via the transcriptional effector Lef1. In contrast the formation of radial glia in the zebrafish hypothalamus does not require Wnt signaling and ectopic Wnt activity reduces their number. This work will test the specific hypotheses that Wnt signaling functions to convert radial glia into neural progenitors, and to promote their proliferative response following injury. First, we will determine whether Wnt signaling is necessary and sufficient to drive radial glia into a neural progenitor state. Second, we will test whether Lef1 promotes neural progenitor formation through downstream targets. Third, we will determine whether Wnt signaling is required for radial glial proliferation after injry. Together, this will characterize the regulation of a novel population of neural progenitors in the vertebrate hypothalamus, and establish a new model for Wnt signaling in CNS neurogenesis.

Public Health Relevance

Injury and disease of the brain are major public health concerns, partly because repair and regeneration of these tissues is limited. Addition of new neurons during life can also impact normal behavior and physiology. This project will add to our understanding of the mechanisms regulating neural stem cells, which produce new neurons in the adult brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS082645-02
Application #
8607219
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Owens, David F
Project Start
2013-03-01
Project End
2018-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
2
Fiscal Year
2014
Total Cost
$616,023
Indirect Cost
$202,585
Name
University of Utah
Department
Biology
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112