""""""""Stem cell research offers enormous potential for treating a host of congenital, developmental, psychiatric or degenerative diseases for which there are no cures (NIH PA-04-101)."""""""" However, a thorough understanding of the molecular mechanisms that regulate adult neural stem cell (NSC) proliferation and differentiation is a pre-requisite for their therapeutic applications. Advances in the stem cell field have expanded our knowledge of transcriptional regulations in adult NSC functions. Recently, microRNA (miRNA) pathway has been shown to play important roles in the proliferation and differentiation of stem cells, indicating that translational regulation of adult NSCs, though less understood, is equally, if not more important in adult NSC function. The long-term goal of this project is to understand the role of translational regulation in adult neurogenesis. Fragile X mental retardation protein (FMRP), the protein that is lost in Fragile X syndrome, is a selective RNA-binding protein that forms a messenger ribonucleoprotein (mRNP) complex associating with polyribosomes. FMRP regulates protein translation and the loss of FMRP leads to abnormal translation of selective mRNAs, delayed maturation of dendritic spines, and abnormal microtubule stability in neurons. We found that FMRP is also highly expressed in neural stem/progenitor cells (NSPCs) derived from adult brains. Our recent studies and those of other groups have demonstrated the biochemical and genetic interactions between FMRP and the components of the miRNA pathway, including Dicer and Argonaute proteins, suggesting that translational regulation of specific mRNAs in adult NSCs could be achieved by collaborative actions between miRNA pathway and FMRP. We have isolated NSPCs from both wild type (wildtype) and Fmr1 knockout (KO) adult mice, and found that the loss of FMRP affects both proliferation and fate- specification of adult NSPCs in vitro. We hypothesize that the proliferation and differentiation of adult NSCs is regulated at the translational level by miRNA pathway and RNA binding protein, FMRP. Therefore, we propose: first to determine whether the translation of NSPC-specific mRNAs is regulated by miRNAs (Aim 1);then to determine whether translational regulation of adult NSCs is critical for NSC function in vivo (Aim 2);and finally to determine whether FMRP and miRNA pathway collaboratively regulate the proliferation and differentiation of adult NSCs (Aim 3). Our proposed work will be carried out by combining the efforts of the PI, Dr. Zhao, who has expertise in adult neurogenesis, and the Co-Pi, Dr. Jin, who has extensive experience in translational regulation and miRNA. The outcome of this work would add a new dimension to our knowledge of NSC regulation in the adult brain. It is our premise that a better understanding of these regulatory mechanisms is a pre-requisite for the therapeutic application of adult NSCs for human diseases.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Beckel-Mitchener, Andrea C
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University of New Mexico
Schools of Medicine
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Sun, Linlin; Zhao, Jian-Yuan; Gu, Xiyao et al. (2017) Nerve injury-induced epigenetic silencing of opioid receptors controlled by DNMT3a in primary afferent neurons. Pain 158:1153-1165
Zhang, Peng; Rausch, Cathia; Hastert, Florian D et al. (2017) Methyl-CpG binding domain protein 1 regulates localization and activity of Tet1 in a CXXC3 domain-dependent manner. Nucleic Acids Res 45:7118-7136
Li, Meng; Zhao, Huashan; Ananiev, Gene E et al. (2017) Establishment of Reporter Lines for Detecting Fragile X Mental Retardation (FMR1) Gene Reactivation in Human Neural Cells. Stem Cells 35:158-169
Jobe, Emily M; Gao, Yu; Eisinger, Brian E et al. (2016) Methyl-CpG binding protein MBD1 regulates neuronal lineage commitment through maintaining adult neural stem cell identity. J Neurosci :
Bhattacharyya, Anita; Zhao, Xinyu (2016) Human pluripotent stem cell models of Fragile X syndrome. Mol Cell Neurosci 73:43-51
Hsieh, Jenny; Zhao, Xinyu (2016) Genetics and Epigenetics in Adult Neurogenesis. Cold Spring Harb Perspect Biol 8:
Li, Yue; Stockton, Michael E; Bhuiyan, Ismat et al. (2016) MDM2 inhibition rescues neurogenic and cognitive deficits in a mouse model of fragile X syndrome. Sci Transl Med 8:336ra61
Chow, Cynthia L; Guo, Weixiang; Trivedi, Parul et al. (2015) Characterization of a unique cell population marked by transgene expression in the adult cochlea of nestin-CreER(T2)/tdTomato-reporter mice. J Comp Neurol 523:1474-87
Wang, Feifei; Tidei, Joseph J; Polich, Eric D et al. (2015) Positive feedback between RNA-binding protein HuD and transcription factor SATB1 promotes neurogenesis. Proc Natl Acad Sci U S A 112:E4995-5004
Gao, Yu; Su, Juan; Guo, Weixiang et al. (2015) Inhibition of miR-15a Promotes BDNF Expression and Rescues Dendritic Maturation Deficits in MeCP2-Deficient Neurons. Stem Cells 33:1618-29

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