Abstract
Fragile X syndrome (FXS), the most common form of inherited mental retardation, is caused by the loss of functional fragile X mental retardation protein (FMRP). FMRP is an RNA–binding protein that can regulate the translation of specific mRNAs. Adult neurogenesis, a process considered important for neuroplasticity and memory, is regulated at multiple molecular levels. In this study, we investigated whether Fmrp deficiency affects adult neurogenesis. We show that in a mouse model of fragile X syndrome, adult neurogenesis is indeed altered. The loss of Fmrp increases the proliferation and alters the fate specification of adult neural progenitor/stem cells (aNPCs). We demonstrate that Fmrp regulates the protein expression of several components critical for aNPC function, including CDK4 and GSK3β. Dysregulation of GSK3β led to reduced Wnt signaling pathway activity, which altered the expression of neurogenin1 and the fate specification of aNPCs. These data unveil a novel regulatory role for Fmrp and translational regulation in adult neurogenesis.
Highlights
Fragile X syndrome, one of the most common forms of inherited mental retardation, is caused by the functional loss of fragile X mental retardation protein (FMRP/Fmrp) [1]
We show that Fmrp could regulate the proliferation and fate specification of adult neural progenitor/stem cells
Both adult hippocampal neurogenesis and learning are altered in several pathological conditions, such as stress, diabetes, neurological diseases, strokes, and traumatic injuries, the link between adult neurogenesis and mental retardation, a deficiency in learning and memory, remains elusive [9,10,11]
Summary
Fragile X syndrome, one of the most common forms of inherited mental retardation, is caused by the functional loss of fragile X mental retardation protein (FMRP/Fmrp) [1]. Patients with fragile X syndrome show an array of deficits in motor control, cognition, learning, and memory, their overall brain morphology is generally normal. Evidence suggests that Fmrp is involved in the post-transcriptional regulation of protein synthesis [2,3,4]. Studies from both human patient brain tissues and Fmrp mutant mice suggest that Fmrp is involved in synaptic plasticity and dendritic development. How the functional deficiency of Fmrp results in learning and memory deficits remains unclear
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