The goal of this proposal is to elucidate cellular and molecular mechanisms that specify the adult stem cell niche (SCN) in the CNS that harbors stem cells throughout life. The SCN is situated in the anterior subventricular zone where newly born neurons derived from adult stem cells migrate through the rostral migratory stream (RMS) to the olfactory bulb (OB) and differentiate into interneurons. The adult SCN consists of astrocytes and ependymal cells that line the ventricular surface of the neostriatum. Both these cell types are derived from an embryonic SCN in the lateral ganglion eminences (LGE). A constellation of transcription factors have been shown to regulate cell fate within distinct domains of the developing LGE. We have identified a fork head transcription factor (FOXJ1) which we show is expressed in a subset of embryonic progenitors in the LGE, and exhibits persistent expression in the postnatal SCN. Our proposed studies will shed light on novel mechanisms underlying differentiation of the SCN, and their concomitant role in regulation of adult stem cells and neurogenesis in the postnatal brain. It is now well established that the timing and proper development of radial glia and their astrocytic progeny are essential for normal CNS development and function. Our studies are unraveling the role of a subset of radial glial cells in the developing LGE which may give rise to a subset of layer specific neurons in the olfactory bulb. While a number of studies have focused on specification of neuronal progeny of radial glial cells in the cerebral cortices, molecular mechanisms that mediate the specification of ependymal cells and a subset of astrocytes that establish the adult SCN are completely unexplored. A comprehensive understanding of these mechanisms is of great interest as their manipulation in adult stem cells and/or the postnatal SCN may allow for production of new neurons and generation of guided neuronal migration to damaged or diseased brain regions, and potential correction of major birth defects such as hydrocephalus.

Public Health Relevance

Our proposed studies will determine novel regulatory mechanisms of a gene that drives the development of a cellular niche for postnatal and adult neural stem cells. Delineation of mechanisms that regulate persistence of regionally specific neurogenesis in the postnatal and adult brain is critical to future application of adult neural stem cells in cell-based therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS062182-01A2
Application #
7785009
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Owens, David F
Project Start
2010-01-18
Project End
2014-11-30
Budget Start
2010-01-18
Budget End
2010-11-30
Support Year
1
Fiscal Year
2010
Total Cost
$322,745
Indirect Cost
Name
North Carolina State University Raleigh
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
042092122
City
Raleigh
State
NC
Country
United States
Zip Code
27695
Davis, Adam; Amin, Nirav M; Johnson, Caroline et al. (2017) Stomach curvature is generated by left-right asymmetric gut morphogenesis. Development 144:1477-1483
Sai, Kazuhito; Morioka, Sho; Takaesu, Giichi et al. (2016) TAK1 determines susceptibility to endoplasmic reticulum stress and leptin resistance in the hypothalamus. J Cell Sci 129:1855-65
Muthusamy, Nagendran; Sommerville, Laura J; Moeser, Adam J et al. (2015) MARCKS-dependent mucin clearance and lipid metabolism in ependymal cells are required for maintenance of forebrain homeostasis during aging. Aging Cell 14:764-73
Hammad, Mohamed; Schmidt, Stephen L; Zhang, Xuying et al. (2015) Transplantation of GABAergic Interneurons into the Neonatal Primary Visual Cortex Reduces Absence Seizures in Stargazer Mice. Cereb Cortex 25:2970-9
Murlidharan, Giridhar; Corriher, Travis; Ghashghaei, H Troy et al. (2015) Unique glycan signatures regulate adeno-associated virus tropism in the developing brain. J Virol 89:3976-87
Muthusamy, Nagendran; Vijayakumar, Akshitha; Cheng Jr, Gang et al. (2014) A knock-in Foxj1(CreERT2::GFP) mouse for recombination in epithelial cells with motile cilia. Genesis 52:350-8
Liang, Huixuan; Xiao, Guanxi; Yin, Haifeng et al. (2013) Neural development is dependent on the function of specificity protein 2 in cell cycle progression. Development 140:552-61
Liang, Huixuan; Hippenmeyer, Simon; Ghashghaei, H Troy (2012) A Nestin-cre transgenic mouse is insufficient for recombination in early embryonic neural progenitors. Biol Open 1:1200-3
Jacquet, Benoit V; Muthusamy, Nagendran; Sommerville, Laura J et al. (2011) Specification of a Foxj1-dependent lineage in the forebrain is required for embryonic-to-postnatal transition of neurogenesis in the olfactory bulb. J Neurosci 31:9368-82
Lim, Ji-Hey; Piedrahita, Jorge A; Jackson, Lauren et al. (2010) Development of a model of sacrocaudal spinal cord injury in cloned Yucatan minipigs for cellular transplantation research. Cell Reprogram 12:689-97

Showing the most recent 10 out of 13 publications