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Abstract
Fragile X related protein 1 (FXR1P) is part of the fragile X family of RNA binding proteins (FXRs), which includes the fragile X mental retardation protein (FMRP) and fragile X related protein 2 (FXR2P). Both FMRP and FXR2P regulate adult neural stem cells (aNSCs) and neurogenesis, a process linked to neurological disorders, such as Fragile X syndrome. Although FXR1P has been implicated in diverse developmental processes and neurological diseases, its role in neurodevelopment is not well-understood. The goal of this study was to elucidate the function of FXR1P in aNSCs and hippocampal neurogenesis. We used a Tamoxifen-inducible triple transgenic mouse model to investigate how Fxr1 deletion affects aNSC proliferation and fate specification. Deletion of Fxr1 resulted in significantly decreased populations of radial glia-like cells, neuroblasts, immature neurons, neurons, and astrocytes. We hypothesized that this reduction in new cell numbers resulted from impaired proliferation, which was confirmed both in vivo and in vitro. We discovered that FXR1P-deficient aNSCs have altered expression of a select number of cell-cycle genes, and identified the mRNA of cyclin-dependent kinase inhibitor 1A (Cdkn1a, p21) as a direct target of FXR1P. Restoration of p21 mRNA to wildtype levels rescued the proliferation deficit in aNSCs lacking FXR1P, demonstrating that p21 is a mediator of FXR1P in aNSCs. Since Fxr1 deletion in aNSCs results in a reduction of new neurons, we also performed behavioral tests for locomotion, anxiety, and hippocampal learning and memory. Although these results are preliminary, it is likely that the loss of FXR1P in aNSCs results in impaired hippocampal-dependent learning and memory.
