In vivo transcriptional profile analysis reveals RNA splicing and chromatin remodeling as prominent processes for adult neurogenesis

The Rockefeller University, New York, New York, United States
Molecular and Cellular Neuroscience (Impact Factor: 3.84). 02/2006; 31(1):131-48. DOI: 10.1016/j.mcn.2005.10.005
Source: PubMed


Neural stem cells and neurogenesis persist in the adult mammalian brain subventricular zone (SVZ). Cells born in the rodent SVZ migrate to the olfactory bulb (Ob) where they differentiate into interneurons. To determine the gene expression and functional profile of SVZ neurogenesis, we performed three complementary sets of transcriptional analysis experiments using Affymetrix GeneChips: (1) comparison of adult mouse SVZ and Ob gene expression profiles with those of the striatum, cerebral cortex, and hippocampus; (2) profiling of SVZ stem cells and ependyma isolated by fluorescent-activated cell sorting (FACS); and (3) analysis of gene expression changes during in vivo SVZ regeneration after anti-mitotic treatment. Gene Ontology (GO) analysis of data from these three separate approaches showed that in adult SVZ neurogenesis, RNA splicing and chromatin remodeling are biological processes as statistically significant as cell proliferation, transcription, and neurogenesis. In non-neurogenic brain regions, RNA splicing and chromatin remodeling were not prominent processes. Fourteen mRNA splicing factors including Sf3b1, Sfrs2, Lsm4, and Khdrbs1/Sam68 were detected along with 9 chromatin remodeling genes including Mll, Bmi1, Smarcad1, Baf53a, and Hat1. We validated the transcriptional profile data with Northern blot analysis and in situ hybridization. The data greatly expand the catalogue of cell cycle components, transcription factors, and migration genes for adult SVZ neurogenesis and reveal RNA splicing and chromatin remodeling as prominent biological processes for these germinal cells.

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Available from: Benedicte Menn
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    • "HMGB2 mRNA was previously reported to be present in the SVZ of P90 adult mice [26]. We verified expression of HMGB2 protein in SVZ progenitor cells in brain sections of young adult Nestin-GFP+ transgenic mice (Fig. S1A–C). "
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    ABSTRACT: Neural stem and progenitor cells (NSCs/NPCs) are distinct groups of cells found in the mammalian central nervous system (CNS). Previously we determined that members of the High Mobility Group (HMG) B family of chromatin structural proteins modulate NSC proliferation and self-renewal. Among them HMGB2 was found to be dynamically expressed in proliferating and differentiating NSCs, suggesting that it may regulate NSC maintenance. We report now that Hmgb2(-/-) mice exhibit SVZ hyperproliferation, increased numbers of SVZ NSCs, and a trend towards aberrant increases in newly born neurons in the olfactory bulb (OB) granule cell layer. Increases in the levels of the transcription factor p21 and the Neural cell adhesion molecule (NCAM), along with down-regulation of the transcription/pluripotency factor Oct4 in the Hmgb2-/- SVZ point to a possible pathway for this increased proliferation/differentiation. Our findings suggest that HMGB2 functions as a modulator of neurogenesis in young adult mice through regulation of NSC proliferation, and identify a potential target via which CNS repair could be amplified following trauma or disease-based neuronal degeneration.
    Full-text · Article · Dec 2013 · PLoS ONE
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    • "In addition to non-covalent chromatin remodeling processes, MLL proteins can catalyze histone 3 lysine 4 trimethylation (H3K4me3) – a mark that is permissive for transcription – and recruit H3K27me3-specific demethylases (Dou et al., 2006; De Santa et al., 2007; Swigut and Wysocka, 2007). Mll1 is expressed in the SVZ lineage, and deletion of Mll1 targeted to SVZ NSCs results in a severe reduction in neurogenesis , but not gliogenesis (Lim et al., 2006). In SVZ monolayer cultures, Mll1-deleted cells proliferate normally and maintain the expression of NSC markers such as Nestin and Sox2. "
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    ABSTRACT: In specific regions of the adult mammalian brain, neural stem cells (NSCs) generate new neurons throughout life. Emerging evidence indicate that chromatin-based transcriptional regulation is a key epigenetic mechanism for the life-long function of adult NSCs. In the adult mouse brain, NSCs in the subventricular zone (SVZ) retain the ability to produce both neurons and glia for the life of the animal. In this review, we discuss the origin and function of SVZ NSCs as they relate to key epigenetic concepts of development and potential underlying mechanism of chromatin-based transcriptional regulation. A central point of discussion is how SVZ NSCs - which possess many characteristics of mature, non-neurogenic astrocytes - maintain a "youthful" ability to produce both neuronal and glial lineages. In addition to reviewing data regarding the function of chromatin-modifying factors in SVZ neurogenesis, we incorporate our growing understanding that long non-coding RNAs serve as an important element to chromatin-based transcriptional regulation, including that of SVZ NSCs. Discoveries regarding the epigenetic mechanisms of adult SVZ NSCs may provide key insights into fundamental principles of adult stem cell biology as well as the more complex and dynamic developmental environment of the embryonic brain.
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    • "did not significantly differ between Brg1 cKO and control mice (Figures S3E and S3F), suggesting that conversion to gliogenesis occurs only when neuronal cells exit the SEZ. This strikingly late fate conversion may be due to a powerful role of the niche environment or other intrinsic mechanisms sufficient to stabilize neuronal fate (Beckervordersandforth et al., 2010; Colak et al., 2008; Lim et al., 2006). To distinguish between these two possibilities, we isolated progenitors from the SEZ of Brg1 cKO or control mice 9 dpt and cultured them in a primary SEZ culture system maintaining neurogenesis (Costa et al., 2011). "
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    ABSTRACT: Numerous transcriptional regulators of neurogenesis have been identified in the developing and adult brain, but how neurogenic fate is programmed at the epigenetic level remains poorly defined. Here, we report that the transcription factor Pax6 directly interacts with the Brg1-containing BAF complex in adult neural progenitors. Deletion of either Brg1 or Pax6 in the subependymal zone (SEZ) causes the progeny of adult neural stem cells to convert to the ependymal lineage within the SEZ while migrating neuroblasts convert to different glial lineages en route to or in the olfactory bulb (OB). Genome-wide analyses reveal that the majority of genes downregulated in the Brg1 null SEZ and OB contain Pax6 binding sites and are also downregulated in Pax6 null SEZ and OB. Downstream of the Pax6-BAF complex, we find that Sox11, Nfib, and Pou3f4 form a transcriptional cross-regulatory network that drives neurogenesis and can convert postnatal glia into neurons. Taken together, elements of our work identify a tripartite effector network activated by Pax6-BAF that programs neuronal fate.
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