Oligodendrocyte development is regulated by the interplay of repressors and activators in a complex transcriptional network. Here we report that two histone-modifying enzymes, HDAC1 and HDAC2, are required for oligodendrocyte formation. Genetic deletion of both HDAC1 and HDAC2 in oligodendrocyte lineage cells resulted in stabilization and nuclear translocation of β-catenin, which negatively regulates oligodendrocyte development by repressing Olig2 expression. We further identified an oligodendrocyte-restricted transcription factor TCF7L2/TCF4 as a bipartite co-effector of β-catenin for regulating oligodendrocyte differentiation. Targeted disruption of TCF7L2 in mice leads to severe defects in oligodendrocyte maturation, while expression of its dominant repressive form promotes precocious oligodendrocyte specification in developing chick neural tube. Transcriptional co-repressors HDAC1 and HDAC2 compete with β-catenin for TCF7L2 interaction to regulate downstream genes involved in oligodendrocyte differentiation. Hence, crosstalk between HDAC1/2 and the canonical Wnt signaling pathway mediated by TCF7L2 serves as a regulatory mechanism for oligodendrocyte differentiation.

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. (t.warashina@aist.go.jp). 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 bHLH transcription factor Olig1 promotes oligodendrocyte maturation and is required for myelin repair. In this report, we characterize an Olig1-regulated G-protein coupled receptor GPR17 whose function is to oppose the action of Olig1. GPR17 is restricted to oligodendrocyte lineage cells but downregulated during the peak period of myelination and in adulthood. Transgenic mice with sustained GPR17 expression in oligodendrocytes exhibit stereotypic features of myelinating disorders in the CNS. GPR17 overexpression inhibits oligodendrocyte differentiation and maturation both in vivo and in vitro. Conversely, GPR17 knockout mice display early onset of oligodendrocyte myelination. The opposing action of GPR17 on oligodendrocyte maturation reflects, at least partially, upregulation and nuclear translocation of the potent oligodendrocyte differentiation inhibitors ID2/4. Collectively, these findings suggest that GPR17 orchestrates the transition between immature and myelinating oligodendrocytes via an ID protein-mediated negative regulation, and may serve as a potential therapeutic target for CNS myelin repair.

The transcriptional program that controls adult neurogenesis is unknown. We generated mice with an inducible stem cell–specific deletion of Neurod1, resulting in substantially fewer newborn neurons in the hippocampus and olfactory bulb. Thus, Neurod1 is cell-intrinsically required for the survival and maturation of adult-born neurons.

Acute seizures after a severe brain insult can often lead to epilepsy and cognitive impairment. Aberrant hippocampal neurogenesis follows the insult but the role of adult-generated neurons in the development of chronic seizures or associated cognitive deficits remains to be determined. Here we show that ablation of adult neurogenesis prior to pilocarpine-induced acute seizures in mice leads to a reduction in chronic seizure frequency. We also show that ablation of neurogenesis normalizes epilepsy-associated cognitive deficits. Remarkably, the effect of ablating adult neurogenesis prior to acute seizures is long-lasting as it suppresses chronic seizure frequency for nearly one year. These findings establish a key role of neurogenesis in chronic seizure development and associated memory impairment and suggest that targeting aberrant hippocampal neurogenesis may reduce recurrent seizures and restore cognitive function following a pro-epileptic brain insult.

Summary An in vivo screen was performed in search of chemicals capable of enhancing neuron formation in the hippocampus of adult mice. Eight of 1,000 small molecules tested enhanced neuron formation in the subgranular zone of the dentate gyrus. Among these was an aminopropyl carbazole, designated P7C3, endowed with favorable pharmacological properties. In vivo studies gave evidence that P7C3 exerts its pro-neurogenic activity by protecting newborn neurons from apoptosis. Mice missing the gene encoding neuronal PAS domain protein 3 (NPAS3) are devoid of hippocampal neurogenesis and display malformation and electrophysiological dysfunction of the dentate gyrus. Prolonged administration of P7C3 to npas3-/- mice corrected these deficits by normalizing levels of apoptosis of newborn hippocampal neurons. Prolonged administration of P7C3 to aged rats also enhanced neurogenesis in the dentate gyrus, impeded neuron death, and preserved cognitive capacity as a function of terminal aging.

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.