BM88/Cend1 Expression Levels Are Critical for Proliferation and Differentiation of Subventricular Zone-Derived Neural Precursor Cells

Laboratory of Cellular and Molecular Neurobiology, Hellenic Pasteur Institute, 127 Vassilissis Sofias Avenue, Athens 115 21, Greece.
Stem Cells (Impact Factor: 6.52). 06/2008; 26(7):1796-807. DOI: 10.1634/stemcells.2007-0921
Source: PubMed


Neural stem cells remain in two areas of the adult mammalian brain, the subventricular zone (SVZ) and the dentate gyrus of the hippocampus. Ongoing neurogenesis via the SVZ-rostral migratory stream pathway maintains neuronal replacement in the olfactory bulb (OB) throughout life. The mechanisms determining how neurogenesis is restricted to only a few regions in the adult, in contrast to its more widespread location during embryogenesis, largely depend on controlling the balance between precursor cell proliferation and differentiation. BM88/Cend1 is a neuronal lineage-specific regulator implicated in cell cycle exit and differentiation of precursor cells in the embryonic neural tube. Here we investigated its role in postnatal neurogenesis. Study of in vivo BM88/Cend1 distribution revealed that it is expressed in low levels in neuronal precursors of the adult SVZ and in high levels in postmitotic OB interneurons. To assess the functional significance of BM88/Cend1 in neuronal lineage progression postnatally, we challenged its expression levels by gain- and loss-of-function approaches using lentiviral gene transfer in SVZ-derived neurospheres. We found that BM88/Cend1 overexpression decreases proliferation and favors neuronal differentiation, whereas its downregulation using new-generation RNA interference vectors yields an opposite phenotype. Our results demonstrate that BM88/Cend1 participates in cell cycle control and neuronal differentiation mechanisms during neonatal SVZ neurogenesis and becomes crucial for the transition from neuroblasts to mature neurons when reaching high levels.

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Available from: Dimitra Thomaidou, Sep 16, 2014
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    • "The expression of NEUROG2 ceases with the onset of the gliogenic period during the late embryonic stage (Ozen et al., 2007). On the other hand, CEND1 is expressed in embryonic and adult NPCs and more strongly in differentiated neurons (Katsimpardi et al., 2008; Politis et al., 2007). It is not expressed in cortical astrocytes either in vivo (Koutmani et al., 2004) or in acute cortical cultures (Figures S1A and S1B). "
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    ABSTRACT: Recent studies demonstrate that astroglia from non-neurogenic brain regions can be reprogrammed into functional neurons through forced expression of neurogenic factors. Here we explored the effect of CEND1 and NEUROG2 on reprogramming of mouse cortical astrocytes and embryonic fibroblasts. Forced expression of CEND1, NEUROG2, or both resulted in acquisition of induced neuronal cells expressing subtype-specific markers, while long-term live-cell imaging highlighted the existence of two different modes of neuronal trans-differentiation. Of note, a subpopulation of CEND1 and NEUROG2 double-transduced astrocytes formed spheres exhibiting neural stem cell properties. mRNA and protein expression studies revealed a reciprocal feedback loop existing between the two molecules, while knockdown of endogenous CEND1 demonstrated that it is a key mediator of NEUROG2-driven neuronal reprogramming. Our data suggest that common reprogramming mechanisms exist driving the conversion of lineage-distant somatic cell types to neurons and reveal a critical role for CEND1 in NEUROG2-driven astrocytic reprogramming. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Stem Cell Reports 08/2015; DOI:10.1016/j.stemcr.2015.07.012 · 5.37 Impact Factor
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    • "Increase in Cend1 expression is functionally associated with down-regulation of cyclin D1 protein levels in proliferating cells both in vitro and in vivo [5,7,12]. The cyclin D1 pathway is critical for cell cycle progression/exit in neuronal precursors, also contributing to survival of newborn neurons [51,52]. "
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    ABSTRACT: BM88/Cend1 is a neuronal-lineage specific modulator with a pivotal role in coordination of cell cycle exit and differentiation of neuronal precursors. In the current study we identified the signal transduction scaffolding protein Ran-binding protein M (RanBPM) as a BM88/Cend1 binding partner and showed that BM88/Cend1, RanBPM and the dual specificity tyrosine-phosphorylation regulated kinase 1B (Dyrk1B) are expressed in mouse brain as well as in cultured embryonic cortical neurons while RanBPM can form complexes with either of the two other proteins. To elucidate a potential mechanism involving BM88/Cend1, RanBPM and Dyrk1B in cell cycle progression/exit, we transiently co-expressed these proteins in mouse neuroblastoma Neuro 2a cells. We found that the BM88/Cend1-dependent or Dyrk1B-dependent down-regulation of cyclin D1 is reversed following their functional interaction with RanBPM. More specifically, functional interaction of RanBPM with either BM88/Cend1 or Dyrk1B stabilizes cyclin D1 in the nucleus and promotes 5-bromo-2'-deoxyuridine (BrdU) incorporation as a measure of enhanced cell proliferation. However, the RanBPM-dependent Dyrk1B cytosolic retention and degradation is reverted in the presence of Cend1 resulting in cyclin D1 destabilization. Co-expression of RanBPM with either BM88/Cend1 or Dyrk1B also had a negative effect on Neuro 2a cell differentiation. Our results suggest that functional interactions between BM88/Cend1, RanBPM and Dyrk1B affect the balance between cellular proliferation and differentiation in Neuro 2a cells and indicate that a potentially similar mechanism may influence cell cycle progression/exit and differentiation of neuronal precursors.
    PLoS ONE 11/2013; 8(11):e82172. DOI:10.1371/journal.pone.0082172 · 3.23 Impact Factor
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    • "For induction of differentiation, single cell-dissociated neurospheres were maintained in the absence of growth factors. Viral transduction was performed as previously described (Katsimpardi et al. 2008; Makri et al. 2010) with slight modifications . Briefly, third passage neurospheres were transduced with Trip.IGF-1 or control Trip.GFP vectors at either the single cell or whole neurosphere stage by exposure for 6–8 h to non-concentrated Trip.IGF-1 or control Trip.GFP viral supernatants. "
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    ABSTRACT: Strategies to enhance neural stem/precursor cell (NPC) capacity to yield multipotential, proliferative, and migrating pools of cells that can efficiently differentiate into neurons could be crucial for structural repair after neurodegenerative damage. Here, we have generated a lentiviral vector for expression of insulin-like growth factor-I (IGF-1) and investigated the impact of IGF-1 transduction on the properties of cultured NPCs (IGF-1-NPCs). Under proliferative conditions, IGF-1 transduction promoted cell cycle progression via cyclin D1 up-regulation and Akt phosphorylation. Remarkably upon differentiation-inducing conditions, IGF-1-NPCs cease to proliferate and differentiate to a greater extent into neurons with significantly longer neurites, at the expense of astrocytes. Moreover, using live imaging we provide evidence that IGF-1 transduction enhances the motility and tissue penetration of grafted NPCs in cultured cortical slices. These results illustrate the important consequence of IGF-1 transduction in regulating NPC functions and offer a potential strategy to enhance the prospective repair potential of NPCs.
    Journal of Neurochemistry 10/2010; 115(2):460-74. DOI:10.1111/j.1471-4159.2010.06939.x · 4.28 Impact Factor
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