DNA methylation-mediated epigenetic regulation plays critical roles in regulating mammalian gene expression, but its role in normal brain function is not clear. Methyl-CpG binding protein 1 (MBD1), a member of the methylated DNA-binding protein family, has been shown to bind methylated gene promoters and facilitate transcriptional repression in vitro. Here we report the generation and analysis of MBD1 ؊/؊ mice. MBD1 ؊/؊ mice had no detectable developmental defects and appeared healthy throughout life. However, we found that MBD1 ؊/؊ neural stem cells exhibited reduced neuronal differentiation and increased genomic instability. Furthermore, adult MBD1 ؊/؊ mice had decreased neurogenesis, impaired spatial learning, and a significant reduction in long-term potentiation in the dentate gyrus of the hippocampus. Our findings indicate that DNA methylation is important in maintaining cellular genomic stability and is crucial for normal neural stem cell and brain functions.
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.
Multipotent neural stem/progenitor cells (NSPCs) can be isolated from many regions of the adult central nervous system (CNS), yet neurogenesis is restricted to the hippocampus and subventricular zone in vivo. Identification of the molecular cues that modulate NSPC fate choice is a prerequisite for their therapeutic applications. We previously demonstrated that primary astrocytes isolated from regions with higher neuroplasticity, such as newborn and adult hippocampus and newborn spinal cord, promoted neuronal differentiation of adult NSPCs, whereas astrocytes isolated from nonneurogenic of the adult spinal cord inhibited neural differentiation. To identify the factors expressed by these astrocytes that could modulate NSPC differentiation, we performed gene expression profiling analysis using Affymetrix rat genome arrays. Our results demonstrated that these astrocytes had distinct gene expression profiles. We further tested the functional effects of candidate factors that were differentially expressed in neurogenesis-promoting and -inhibiting astrocytes using in vitro NSPC differentiation assays. Our results indicated that two interleukins, IL-1β and IL-6, and a combination of factors that included these two interleukins could promote NSPC neuronal differentiation, whereas insulin-like growth factor binding protein 6 (IGFBP6) and decorin inhibited neuronal differentiation of adult NSPCs. Our results have provided further evidence to support the ongoing hypothesis that, in adult mammalian brains, astrocytes play critical roles in modulating NSPC differentiation. The finding that cytokines and chemokines expressed by astrocytes could promote NSPC neuronal differentiation may help us to understand how injuries induce neurogenesis in adult brains.
It is well known that Rett Syndrome, a severe postnatal childhood neurological disorder is mostly caused by mutations in the MECP2 gene. However, how deficiencies in MeCP2 contribute to the neurological dysfunction of Rett Syndrome is not clear. We aimed to resolve the role of MeCP2 epigenetic regulation in postnatal brain development in a Mecp2-deficient mouse model. We found that, while Mecp2 was not critical for the production of immature neurons in the dentate gyrus (DG) of the hippocampus, the newly generated neurons exhibited pronounced deficits in neuronal maturation, including delayed transition into a more mature stage, altered expression of presynaptic proteins, and reduced dendritic spine density. Furthermore, analysis of gene expression profiles of isolated DG granule neurons revealed abnormal expression levels of a number of genes previously shown to be important for synaptogenesis. Our studies suggest that MeCP2 plays a central role in neuronal maturation, which might be mediated through epigenetic control of expression pathways that are instrumental in both dendritic development and synaptogenesis.
STEM CELLS 2008;26:3139 -3149 Disclosure of potential conflicts of interest is found at the end of this article.
Whether and how mechanisms intrinsic to stem cells modulate their proliferation and differentiation are two central questions in stem cell biology. Although exogenous basic fibroblast growth factor 2 (FGF-2/Fgf-2) is commonly used to expand adult neural stem/progenitor cells (NSPCs) in vitro, we do not yet understand the functional significance or the molecular regulation of Fgf-2 expressed endogenously by adult NSPCs. We previously demonstrated that methylated CpG binding protein 1 (MBD1/Mbd1) is a transcriptional repressor of Fgf-2 and is enriched in adult brains. Mbd1 deficiency in mice selectively affected adult neurogenesis and the differentiation of NSPCs. Here we show that an Mbd1 and DNA methylation-mediated epigenetic mechanism regulated the expression of stem cell mitogen Fgf-2 in adult NSPCs. Mbd1 bound to the Fgf-2 promoter and regulates its expression in adult NSPCs. In the absence of functional Mbd1, the Fgf-2 promoter was hypomethylated, and treatment with a DNA methylation inhibitor resulted in increased Fgf-2 expression in adult NSPCs. We further demonstrated that both acute knockdown of Mbd1 or overexpression of Fgf-2 in adult NSPCs inhibited their neuronal differentiation, which could be responsible for the neurogenic deficits observed in Mbd1-deficient mice. These data indicate that intrinsic epigenetic mechanisms play critical roles in the regulation of adult NSPC functions.Neurogenesis is a critical component of neuroplasticity in the adult brain, and its discovery presents exciting prospects for neural repair (1). Ample experimental evidence indicates that the extrinsic environment ("stem cell niche") regulates the fate of adult neural stem/progenitor cells (NSPCs) 3 (2). On the other hand, the intrinsic genetic and epigenetic mechanisms that modulate adult NSPC functions, although of potentially equal importance (3), are not fully clear (4). FGF-2 is an essential growth factor for neural development and neurogenesis (5-7). Recombinant FGF-2 can expand and maintain the undifferentiated state of isolated adult NSPCs (7-9). However, whether adult NSPCs express FGF-2, how that expression might be regulated, and the functional significance of endogenously expressed FGF-2 in adult NSPC biology remain to be investigated.Epigenetic mechanisms, including DNA methylation, chromatin remodeling, and the noncoding RNA-mediated process, play profound regulatory roles in mammalian gene expression (10). Differential methylation at promoters is involved in the regulation of gene expression, and altered promoter methylation levels are molecular signatures for conditions ranging from cancers to psychiatric disorders (11, 12). MBD1 contains several functional domains that allow it to bind both methylated and unmethylated CpGs and subsequently repress gene expression (13). Earlier we showed that MBD1 is a transcriptional repressor for FGF-2 in human glioma cells (14). We then found that Mbd1 is expressed in adult NSPCs, and mice lacking functional Mbd1 (Mbd1 Ϫ/Ϫ or KO) exhibited deficits in adult neurogenesis...
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