Regulation of Cerebral Cortical Size by Control of Cell Cycle Exit in Neural Precursors

Brigham and Women's Hospital, Boston, Massachusetts, United States
Science (Impact Factor: 33.61). 08/2002; 297(5580):365-9. DOI: 10.1126/science.1074192
Source: PubMed


Transgenic mice expressing a stabilized beta-catenin in neural precursors develop enlarged brains with increased cerebral cortical surface area and folds resembling sulci and gyri of higher mammals. Brains from transgenic animals have enlarged lateral ventricles lined with neuroepithelial precursor cells, reflecting an expansion of the precursor population. Compared with wild-type precursors, a greater proportion of transgenic precursors reenter the cell cycle after mitosis. These results show that beta-catenin can function in the decision of precursors to proliferate or differentiate during mammalian neuronal development and suggest that beta-catenin can regulate cerebral cortical size by controlling the generation of neural precursor cells.

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Available from: Anjen Chenn, Oct 05, 2015
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    • "Knockdown of GPR50 results in suppressing neuronal differentiation and self-renewal, which is accompanied with increased hes1 and decreased TCF7L2 expression. Both pathways promote self-renewal through enhancing cyclin D1 transcription [20] [21] [28]. It seems that decreased TCF7L2 overrides the effects of increased hes1 on self-renewal of NPCs. "
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    ABSTRACT: G protein-coupled receptor 50 (GPR50), a risk factor for major depressive disorder and bipolar affective disorder, is expressed in both the developmental and adult brain. However, the function of GPR50 in the brain remains unknown. We here show GPR50 is expressed by neural progenitor cells (NPCs) in the ventricular zone of embryonic brain. Knockdown of GPR50 with a small interference RNA (siRNA) decreased self-renewal and neuronal differentiation, but not glial differentiation of NPCs. Moreover, overexpression of either full-length GPR50 or the intracellular domain of GPR50, rather than the truncated GPR50 in which the intracellular domain is deleted in, increased neuronal differentiation, indicating that GPR50 promotes neuronal differentiation of NPCs in an intracellular domain-dependent manner. We further described that the transcriptional activity of the intracellular domain of notch on Hes1 gene was repressed by overexpression of GPR50. In addition, decreased levels of transcription factor 7-like 2 (TCF7L2) mRNA was observed in GPR50 siRNA-transfected NPCs, suggesting that knockdown of GPR50 impairs wnt/β-catenin signaling. Moreover, the mRNA levels of neurogenin (Ngn) 1, Ngn2 and cyclin D1, the target genes of notch and wnt/β-catenin signalings, in NPCs were reduced by knockdown of GPR50. Therefore, GPR50 promotes self-renewal and neuronal differentiation of NPCs possibly through regulation of notch and wnt/β-catenin signalings. Copyright © 2015. Published by Elsevier Inc.
    Biochemical and Biophysical Research Communications 02/2015; 458(4). DOI:10.1016/j.bbrc.2015.02.040 · 2.30 Impact Factor
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    • "This view of gyrification as the aggregate of multiple factors which contribute to surface expansion fits with observations of how genes and transcription factors (TFs) variously induce morphological abnormalities. These have been extensively reviewed elsewhere (Hevner 2006), but point to the general principle that those factors which promote surface expansion through an increase in progenitor proliferation (in particular proliferation of radial glia) result in an increase in surface expansion and hence gyrification (Chenn and Walsh 2002). For example, FGF2, the manipulation of which can be used to induce folding, promotes RG self-renewal leading to an increase in tangential cortical expansion (Rash et al. 2013). "
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    ABSTRACT: Cortical gyrification is not a random process. Instead, the folds that develop are synonymous with the functional organization of the cortex, and form patterns that are remarkably consistent across individuals and even some species. How this happens is not well understood. Although many developmental features and evolutionary adaptations have been proposed as the primary cause of gyrencephaly, it is not evident that gyrification is reducible in this way. In recent years, we have greatly increased our understanding of the multiple factors that influence cortical folding, from the action of genes in health and disease to evolutionary adaptations that characterize distinctions between gyrencephalic and lissencephalic cortices. Nonetheless it is unclear how these factors which influence events at a small-scale synthesize to form the consistent and biologically meaningful large-scale features of sulci and gyri. In this article, we review the empirical evidence which suggests that gyrification is the product of a generalized mechanism, namely the differential expansion of the cortex. By considering the implications of this model, we demonstrate that it is possible to link the fundamental biological components of the cortex to its large-scale pattern-specific morphology and functional organization.
    Brain Structure and Function 12/2014; 220(5). DOI:10.1007/s00429-014-0961-z · 5.62 Impact Factor
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    • "Importantly , in vivo expression of GSK - 3 cannot be inhibited by serine - phosphorylation – impaired neurogenesis in mice and blocked the enhancement of neuro - genesis induced by co - administration of lithium and fluoxetine ( Eom and Jope , 2009 ) . Moreover , in adult transgenic mice that express the stabilized form of β - catenin , which lacks the GSK - 3β phosphorylation site , the SVZ is enlarged ( Chenn and Walsh , 2002 ) . Retroviral - mediated expression of a stabilized β - catenin protein or administration of a specific inhibitor of GSK - 3β pro - moted the proliferation of progenitor cells in the adult mouse brain ( Adachi et al . "
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    ABSTRACT: It is generally accepted that chronic treatment with antidepressants increases hippocampal neurogenesis, but the molecular mechanisms underlying their effects are unknown. Recently, glycogen synthase kinase-3 beta (GSK-3β)/β-catenin signalling was shown to be involved in the mechanism of how antidepressants might influence hippocampal neurogenesis. The aim of this study was to determine whether GSK-3β/β-catenin signalling is involved in the alteration of neurogenesis as a result of treatment with fluoxetine, a selective serotonin reuptake inhibitor. The mechanisms involved in fluoxetine's regulation of GSK-3β/β-catenin signalling pathway were also examined. Our results demonstrated that fluoxetine increased the proliferation of embryonic neural precursor cells (NPCs) by upregulating the phosphorylation of Ser9 on GSK-3β and increasing the level of nuclear β-catenin. The overexpression of a stabilised β-catenin protein (ΔN89 β-catenin) significantly increased NPC proliferation, while inhibition of β-catenin expression in NPCs led to a significant decrease in the proliferation and reduced the proliferative effects induced by fluoxetine. The effects of fluoxetine-induced upregulation of both phosphorylation of Ser9 on GSK-3β and nuclear β-catenin were significantly prevented by the 5-hydroxytryptamine-1A (5-HT1A) receptor antagonist WAY-100635. The results demonstrate that fluoxetine may increase neurogenesis via the GSK-3β/β-catenin signalling pathway that links postsynaptic 5-HT1A receptor activation. © The Author 2014. Published by Oxford University Press on behalf of CINP.
    The International Journal of Neuropsychopharmacology 12/2014; 18(5). DOI:10.1093/ijnp/pyu099 · 4.01 Impact Factor
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