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

Department of Neurological Surgery and Developmental and Stem Cell Biology Program, University of California, San Francisco, CA 94143, USA.
Molecular and Cellular Neuroscience (Impact Factor: 3.84). 02/2006; 31(1):131-48. DOI: 10.1016/j.mcn.2005.10.005
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Benedicte Menn, Sep 27, 2015
23 Reads
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    PLoS ONE 12/2013; 8(12):e84838. DOI:10.1371/journal.pone.0084838 · 3.23 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    Frontiers in Genetics 10/2013; 4:194. DOI:10.3389/fgene.2013.00194
  • Source
    • "A recent study in zebrafish reported that HMGB1 is critical for early brain development, since morpholino-knockdown of HMGB1 expression created forebrain defects and ablation of the catecholamine network [22]. HMGB2 is expressed 17-fold higher in the SVZ stem cell niche than in the olfactory bulb (OB) [23], suggesting a specific role for HMGB2 in SVZ NSC proliferation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Neural Stem Cells (NSCs) are a distinct group of cells present in the embryonic and adult mammalian central nervous system (CNS) that are able to differentiate into neurons, astrocytes and oligodendrocytes. As NSC proliferation declines with age, factors that regulate this process need to be defined. To search for NSC regulatory factors, we performed a quantitative shotgun proteomics study that revealed that members of the High Mobility Group B (HMGB) family are highly expressed in NSCs. Using a neurosphere assay, we report the differential expression of HMGB1, 2, 3, and 4 mRNAs in proliferating NSCs isolated from various time points during embryonic development, as well as the dynamic expression of HMGB1 and B2 mRNAs and proteins in differentiating embryonic NSCs. Expression of HMGB2 underwent the most dramatic changes during the developmental ages examined; as a result, we assessed its role in NSC proliferation and differentiation. We report the predominance of small diameter HMGB2-/- neurospheres in comparison to wild-type, which correlated with increased proliferation in these smaller HMGB2-/- neurospheres. Our data suggest that HMGB2 plays a regulatory role in NSC cell proliferation and maintenance pathways.
    Proteome Science 04/2013; 11(1):18. DOI:10.1186/1477-5956-11-18 · 1.73 Impact Factor
Show more