Neural stem cells exist in the adult brain and continually generate new neurons, which respond to multiple physiological and pathological stimulations and are potentially involved in learning and memory, epilepsy, depression, and brain remodeling after injury. Most recent data also demonstrate an interconnection between neural stem cells and deadly brain tumors. The long-term goal of this application is to understand the regulation of adult neural stem cells and their roles under normal or diseased conditions. As integrators of multiple extracellular and intracellular signaling pathways and through direct interaction with the genome, transcription factors play key roles in cell type specification, proliferation, and differentiation. Our research will use one of these transcription factors as a molecular tool. We and others demonstrated that orphan nuclear receptor TLX (NR2E1) is absolutely required for the maintenance and proliferation of adult neural stem cells in neurogenic niches. We further showed that TLX-dependent adult neurogenesis contributes to spatial learning and memory. By employing the most advanced molecular, cellular and mouse genetic approaches, the studies described here seek to understand: 1) the transcriptional logic underlying the specification and maintenance of neural stem cells;and 2) the role of TLX-dependent neural stem cells in brain-related diseases. Results from this work will provide novel insights into our understanding of the biology of neural stem cells and their role under diseased conditions. Such knowledge will be pivotal to fulfill the promise of targeting these stem cells for therapeutics.

Public Health Relevance

The existence of neural stem cells in the adult brain generates great hope for regenerative therapy for certain brain injuries, neurodegeneration, and depression. Concomitantly, these cells may be the cause and perpetuator of deadly brain tumors. Our proposed research will focus on understanding the regulation and function of adult neural stem cells under normal and disease conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS070981-04
Application #
8659519
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Owens, David F
Project Start
2011-07-01
Project End
2016-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
4
Fiscal Year
2014
Total Cost
$344,335
Indirect Cost
$127,772
Name
University of Texas Sw Medical Center Dallas
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Liu, Meng-Lu; Zang, Tong; Zhang, Chun-Li (2016) Direct Lineage Reprogramming Reveals Disease-Specific Phenotypes of Motor Neurons from Human ALS Patients. Cell Rep 14:115-28
Smith, Derek K; Wang, Lei-Lei; Zhang, Chun-Li (2016) Physiological, pathological, and engineered cell identity reprogramming in the central nervous system. Wiley Interdiscip Rev Dev Biol 5:499-517
Zhi, Xiaoyong; Zhou, X Edward; He, Yuanzheng et al. (2015) Structural basis for corepressor assembly by the orphan nuclear receptor TLX. Genes Dev 29:440-50
Chen, Gong; Wernig, Marius; Berninger, Benedikt et al. (2015) In Vivo Reprogramming for Brain and Spinal Cord Repair. eNeuro 2:
Islam, Mohammed M; Zhang, Chun-Li (2015) TLX: A master regulator for neural stem cell maintenance and neurogenesis. Biochim Biophys Acta 1849:210-6
Beckervordersandforth, Ruth; Zhang, Chun-Li; Lie, Dieter Chichung (2015) Transcription-Factor-Dependent Control of Adult Hippocampal Neurogenesis. Cold Spring Harb Perspect Biol 7:a018879
Islam, Mohammed M; Smith, Derek K; Niu, Wenze et al. (2015) Enhancer Analysis Unveils Genetic Interactions between TLX and SOX2 in Neural Stem Cells and In Vivo Reprogramming. Stem Cell Reports 5:805-15
Niu, Wenze; Zang, Tong; Smith, Derek K et al. (2015) SOX2 reprograms resident astrocytes into neural progenitors in the adult brain. Stem Cell Reports 4:780-94
Smith, Derek K; Zhang, Chun-Li (2015) Regeneration through reprogramming adult cell identity in vivo. Am J Pathol 185:2619-28

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