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Geminin-deficient neural stem cells exhibit normal cell division and normal neurogenesis.

ABSTRACT: Neural stem cells (NSCs) are the progenitors of neurons and glial cells during both embryonic development and adult life. The unstable regulatory protein Geminin (Gmnn) is thought to maintain neural stem cells in an undifferentiated state while they proliferate. Geminin inhibits neuronal differentiation in cultured cells by antagonizing interactions between the chromatin remodeling protein Brg1 and the neural-specific transcription factors Neurogenin and NeuroD. Geminin is widely expressed in the CNS during throughout embryonic development, and Geminin expression is down-regulated when neuronal precursor cells undergo terminal differentiation. Over-expression of Geminin in gastrula-stage Xenopus embryos can expand the size of the neural plate. The role of Geminin in regulating vertebrate neurogenesis in vivo has not been rigorously examined. To address this question, we created a strain of Nestin-Cre/Gmnn(fl/fl) mice in which the Geminin gene was specifically deleted from NSCs. Interestingly, we found no major defects in the development or function of the central nervous system. Neural-specific Gmnn(?/?) mice are viable and fertile and display no obvious neurological or neuroanatomical abnormalities. They have normal numbers of BrdU(+) NSCs in the subgranular zone of the dentate gyrus, and Gmnn(?/?) NSCs give rise to normal numbers of mature neurons in pulse-chase experiments. Gmnn(?/?) neurosphere cells differentiate normally into both neurons and glial cells when grown in growth factor-deficient medium. Both the growth rate and the cell cycle distribution of cultured Gmnn(?/?) neurosphere cells are indistinguishable from controls. We conclude that Geminin is largely dispensable for most of embryonic and adult mammalian neurogenesis.

SUBMITTER: Schultz KM

PROVIDER: S-EPMC3052383 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Geminin-deficient neural stem cells exhibit normal cell division and normal neurogenesis.

Schultz Kathryn M KM Banisadr Ghazal G Lastra Ruben O RO McGuire Tammy T Kessler John A JA Miller Richard J RJ McGarry Thomas J TJ

PloS one 20110309 3

Neural stem cells (NSCs) are the progenitors of neurons and glial cells during both embryonic development and adult life. The unstable regulatory protein Geminin (Gmnn) is thought to maintain neural stem cells in an undifferentiated state while they proliferate. Geminin inhibits neuronal differentiation in cultured cells by antagonizing interactions between the chromatin remodeling protein Brg1 and the neural-specific transcription factors Neurogenin and NeuroD. Geminin is widely expressed in th ...[more]

PMID: 21408022

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Project description:Regulating the transition from lineage-restricted progenitors to terminally differentiated cells is a central aspect of nervous system development. Here, we investigated the role of the nucleoprotein Geminin in regulating neurogenesis at a mechanistic level during both Xenopus primary neurogenesis and mammalian neuronal differentiation in vitro. The latter work utilized both neural cells derived from embryonic stem and embryonal carcinoma cells in vitro and neural stem cells from mouse forebrain. In all of these contexts, Geminin antagonized the ability of neural bHLH transcription factors to activate transcriptional programs promoting neurogenesis. Furthermore, Geminin promoted a bivalent chromatin state, characterized by the presence of both activating and repressive histone modifications, at genes encoding transcription factors that promote neurogenesis. This epigenetic state restrains the expression of genes that regulate commitment of undifferentiated stem and neuronal precursor cells to neuronal lineages. Geminin is highly expressed in undifferentiated neuronal precursor cells but is downregulated prior to differentiation. Therefore, these data support a model whereby Geminin promotes the neuronal precursor cell state by modulating both the epigenetic status and expression of genes encoding neurogenesis-promoting factors. Additional developmental signals acting in these cells can then control their transition toward terminal neuronal or glial differentiation during mammalian neurogenesis. A mouse embryonic stem (ES) cell line for inducible knockdown of the small nucleoprotein Geminin was utilized. ES cells were used to generate neural precursor cells by monolayer culture in N2B27 media for 5 days, and doxycycline-inducible knockdown of Geminin was performed from day 3. Changes in gene expression resulting from Geminin knockdown were assessed by RNA sequencing. Three experimental replicates were generated for Geminin knockdown (plus Dox) with a corresponding no-Dox control. These were subjected to sequencing, and data were analyzed using TopHat and Cufflinks/Cuffdiff. Transcripts were considered as differentially expressed upon Gem knockdown if data met statistical significance cutoffs in Cuffdiff (sufficient sequence alignments were obtained for analysis and transcript had significant change in FPKM value (normalized transcript abundance; fragments per kb of exon per million fragments mapped) between the no Dox and plus Dox sample pairs) in at least two of the three replicates.

Dataset Information

Geminin-deficient neural stem cells exhibit normal cell division and normal neurogenesis.

Publications

Geminin-deficient neural stem cells exhibit normal cell division and normal neurogenesis.

Similar Datasets

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