It has become apparent that chromatin modification plays a critical role in the regulation of cell-type-specific gene expression. Here, we show that an inhibitor of histone deacetylase, valproic acid (VPA), induced neuronal differentiation of adult hippocampal neural progenitors. In addition, VPA inhibited astrocyte and oligodendrocyte differentiation, even in conditions that favored lineagespecific differentiation. Among the VPA-up-regulated, neuronspecific genes, a neurogenic basic helix-loop-helix transcription factor, NeuroD, was identified. Overexpression of NeuroD resulted in the induction and suppression of neuronal and glial differentiation, respectively. These results suggest that VPA promotes neuronal fate and inhibits glial fate simultaneously through the induction of neurogenic transcription factors including NeuroD.cell fate specification ͉ chromatin ͉ neural stem cell ͉ valproic acid
In adult hippocampus, new neurons are continuously generated from neural stem cells (NSCs), but the molecular mechanisms regulating adult neurogenesis remain elusive. We found that Wnt signaling, together with the removal of Sox2, triggered the expression of NeuroD1 in mice. This transcriptional regulatory mechanism was dependent on a DNA element containing overlapping Sox2 and T-cell factor/lymphoid enhancer factor (TCF/LEF)-binding sites (Sox/LEF) in the promoter. Notably, Sox/LEF sites were also found in long interspersed nuclear element 1 (LINE-1) elements, consistent with their critical roles in the transition of NSCs to proliferating neuronal progenitors. Our results describe a previously unknown Wnt-mediated regulatory mechanism that simultaneously coordinates activation of NeuroD1 and LINE-1, which is important for adult neurogenesis and survival of neuronal progenitors. Moreover, the discovery that LINE-1 retro-elements embedded inCorrespondence should be addressed to T.K. (email@example.com). 8 Present address: Cell Biology Research Center, Genome Research Laboratories, Wako Pure Chemical Industries, Ltd., Amagasaki, Hyogo, Japan. 9 These authors contributed equally to this work.Note: Supplementary information is available on the Nature Neuroscience website. AUTHOR CONTRIBUTIONS NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript the mammalian genome can function as bi-directional promoters suggests that Sox/LEF regulatory sites may represent a general mechanism, at least in part, for relaying environmental signals to other nearby loci to promote adult hippocampal neurogenesis.In the neurogenic niche of the adult mammalian brain, self-renewing NSCs give rise to committed neuronal progenitors in the subgranular zone (SGZ) of the dentate gyrus 1 .Astrocytes are an essential cell population that defines the SGZ niche and astrocyte-derived factors have instructive effects to promote adult neurogenesis 2,3 . Recently, it has been shown that Wnt3 expression persists in the adult hippocampus and Wnt3 is released by astrocytes to regulate adult neurogenesis in vitro and in vivo 4 . In the canonical Wnt/β-catenin pathway, the TCF transcription factor transduces Wnt/β-catenin signals to activate downstream target genes 4-9 . However, the target genes of Wnt/β-catenin signaling that are responsible for promoting adult neurogenesis have not been identified. Moreover, the regulatory mechanism underlying Wnt-mediated neuronal differentiation has not yet been elucidated.NeuroD1 is a proneural basic helix-loop-helix (bHLH) transcription factor that is essential for the development of the CNS, particularly for the generation of granule cells in the hippocampus and cerebellum 10,11 . Environmental signals regulate adult neurogenesis, at least in part, through the activation of NeuroD1 (refs. 12,13 Here, we found that the transcriptional activation of NeuroD1 is dependent on canonical Wnt/ β-catenin activation and removal of Sox2 repression from the Neurod1 promoter in a sequencespeci...
The central nervous system (CNS) is arguably one of the most complex systems in the universe. To understand the CNS, scientists have investigated a variety of molecules, including proteins, lipids, and various small molecules. However, one large class of molecules, noncoding RNAs (ncRNAs), has been relatively unexplored. ncRNAs function directly as structural, catalytic, or regulatory molecules rather than serving as templates for protein synthesis. The increasing variety of ncRNAs being identified in the CNS suggests a strong connection between the biogenesis, dynamics of action, and combinatorial regulatory potential of ncRNAs and the complexity of the CNS. In this review, we give an overview of the diversity and abundance of ncRNAs before delving into specific examples that illustrate their importance in the CNS. In particular, we cover recent evidence for the roles of microRNAs, small nucleolar RNAs, retrotransposons, the NRSE small modulatory RNA, and BC1/BC200 in the CNS. Finally, we speculate why ncRNAs are well adapted to improving organism-environment interactions.
Discovering the molecular mechanisms that regulate neuron-specific gene expression remains a central challenge for CNS research. Here, we report that small, noncoding double-stranded (ds) RNAs play a critical role in mediating neuronal differentiation. The sequence defined by this dsRNA is NRSE/RE1, which is recognized by NRSF/REST, known primarily as a negative transcriptional regulator that restricts neuronal gene expression to neurons. The NRSE dsRNA can trigger gene expression of neuron-specific genes through interaction with NRSF/REST transcriptional machinery, resulting in the transition from neural stem cells with neuron-specific genes silenced by NRSF/REST into cells with neuronal identity that can express neuronal genes. The mechanism of action appears to be mediated through a dsRNA/protein interaction, rather than through siRNA or miRNA. The discovery of small modulatory dsRNAs (smRNAs) extends the important contribution of noncoding RNAs as key regulators of cell behavior at both transcriptional and posttranscriptional levels.
Adult multipotent neural progenitor cells can differentiate into neurons, astrocytes, and oligodendrocytes in the mammalian central nervous system, but the molecular mechanisms that control their differentiation are not yet well understood. Insulin-like growth factor I (IGF-I) can promote the differentiation of cells already committed to an oligodendroglial lineage during development. However, it is unclear whether IGF-I affects multipotent neural progenitor cells. Here, we show that IGF-I stimulates the differentiation of multipotent adult rat hippocampus-derived neural progenitor cells into oligodendrocytes. Modeling analysis indicates that the actions of IGF-I are instructive. Oligodendrocyte differentiation by IGF-I appears to be mediated through an inhibition of bone morphogenetic protein signaling. Furthermore, overexpression of IGF-I in the hippocampus leads to an increase in oligodendrocyte markers. These data demonstrate the existence of a single molecule, IGF-I, that can influence the fate choice of multipotent adult neural progenitor cells to an oligodendroglial lineage.
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.
We have constructed an allosterically controllable novel enzyme (designated maxizyme) that can be transcribed in vivo under the control of a human tRNA(Val) promoter. The maxizyme has sensor arms that can recognize target sequences, and in the presence of such a target sequence only, it can form a cavity that can capture catalytically indispensable Mg2+ ions. As a target for a demonstration of the potential utility of the maxizyme, we chose BCR-ABL mRNA, the translated products of which cause chronic myelogenous leukemia. Only the maxizyme (but not conventional ribozymes) had extremely high specificity and high-level activity, not only in vitro but also in cultured cells including BV173 cells derived from a patient with a Philadelphia chromosome. The maxizyme induced apoptosis only in leukemic cells with this chromosome.
The mammalian brain contains neural stem cells (NSCs) that enable continued neurogenesis throughout adulthood. However, NSC function and/or numbers decline with increasing age. Adult hippocampal neurogenesis is unique in that astrocytes secreting Wnt3 promote NSC differentiation in a paracrine manner. Here, we show that both the levels of Wnt3 protein and the number of Wnt3-secreting astrocytes influence the impairment of adult neurogenesis during aging. The age-associated reduction in Wnt3 levels affects the regulation of target genes, such as NeuroD1 and retrotransposon L1, as well as the expression of Dcx, which is located adjacent to the L1 loci. Interestingly, the decline in the extrinsic Wnt3 levels and in the intracellular expression of the target genes with aging was reversible. Exercise was found to significantly increase de novo expression of Wnt3 and thereby rescue impaired neurogenesis in aged animals. Furthermore, the chromatin state of NeuroD1, L1, and the L1 loci near Dcx changed relative to Wnt3 levels in an age- or stimulus-associated manner. These results suggest that the regulation of paracrine factors plays a critical role in hippocampal aging and neurogenesis.
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