Translational Regulation of Adult Neural Stem Cells

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DESCRIPTION (provided by applicant): Neural stem/progenitor cells (NSCs) in postnatal and adult brains may play a major role in both normal brain functions, such as learning and memory, as well as the brain's response to injury and disease. Understanding NSCs and adult neurogenesis holds the key to therapeutic applications of not only NSCs but also many other types of stem cells. In addition, NSCs make an excellent model system for studying neurodevelopment and related disorders with postnatal etiology, such as autism spectrum disorders. Our ultimate goal is to reveal mechanisms regulating NSCs and uncover new therapeutic targets for treating mental disorders. Neurogenesis is defined as generation and maturation of new neurons. Although the specific purpose of adult neurogenesis is not entirely clear, work from ours and others' have provided evidence supporting its important roles in adult neuroplasticity and hippocampus-dependent learning. Both adult hippocampal neurogenesis and learning are altered in a number of pathological conditions. However how they contribute to human intellectual disability, a deficiency in learning and memory, is still unclear. Fragile X mental retardation protein (FMRP) is a neuron- enriched selective RNA-binding protein associated with polyribosomes and it is known to regulate protein translation. Functional loss of FMRP leads to Fragile X syndrome, most common monogenetic form of inherited intellectual disability and autism, with learning disability. Despite extensive effort, the mechanisms underlying the learning deficits in Fragile X syndrome remain unclear. During the current funding period, we have found that FMRP is highly expressed in adult NSCs and regulates the translational of several proteins involved in NSC fate specification. Using null and conditional inducible mouse genetics, we have demonstrated that FMRP deficiency impairs both hippocampal neurogenesis and hippocampus-dependent learning (PloS Genet 2010; Nat Med 2011). In addition, manipulation of FMRP-regulated pathways, such as treatment by a Gsk3¿ inhibitor, rescues both neurogenesis and learning deficits of FMRP null mice (Hum Mol Genet 2011). These data provide direct evidence for the role of FMRP in postnatal neurogenesis and learning and present us a unique opportunity for understanding the specific roles and functional impact of RNA binding protein- mediated translational regulation in postnatal/adult neurogenesis and learning disabilities. Built upon these exciting data and our strength, the current proposal aims to test the hypothesis that FMRP regulates multiple stages of adult neurogenesis and its deficiency disrupts the development and impairs the function of new neurons. To test this hypothesis, we will define the roles of FMRP in stem and progenitor cells in the adult DG (Aim 1); determine specific function of FMRP in new DG neurons (Aim 2); and determine the mechanism underlying FMRP regulation of adult neurogenesis (Aim 3). These data will provide critical information regarding not only the function of FMRP in neurogenesis but also the function of stage-specific neurogenesis in learning and memory.