The cell biology of neural stem and progenitor cells and its significance for their proliferation versus differentiation during mammalian brain development

Farkas, Lilla M.; Huttner, Wieland B.

doi:10.1016/j.ceb.2008.09.008

Cited by 220 publications

(173 citation statements)

References 62 publications

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“…The neuroepithelium of developing mammalian brains has a string of adherens junctions that connects neural progenitors at the ventricular surface, similar to apical epithelial junctions (4). The main building blocks of adherens junctions are cadherins and catenins, and in the developing mammalian brains, the critical components are N-cadherin, β-catenin, and αE-catenin, according to their unique gene-expression patterns and null-mutation phenotypes (5).…”

Section: Discussionmentioning

confidence: 99%

“…Apart from maintaining intercellular adhesion, adherens junctions that are preferentially located at the ventricular surface of the neuroepithelium are linked to several major signaling pathways to regulate the rate and mode of cell division in neural progenitors (4,5). Classic cadherins are core components of adherens junctions.…”

Section: Cns Development | Cell Adhesionmentioning

confidence: 99%

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Loss of RhoA in neural progenitor cells causes the disruption of adherens junctions and hyperproliferation

Katayama

Meléndez

Baumann

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

101

138

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The organization of neural progenitors in the developing mammalian neuroepithelium is marked by cadherin-based adherens junctions. Whereas RhoA, a founding member of the small Rho GTPase family, has been shown to play important roles in epithelial adherens junctions, its physiological roles in neural development remain uncertain due to the lack of specific loss-of-function studies. Here, we show that RhoA protein accumulates at adherens junctions in the developing mouse brain and colocalizes to the cadherin–catenin complex. Conditional deletion of RhoA in midbrain and forebrain neural progenitors using Wnt1-Cre and Foxg1-Cre mice, respectively, disrupts apical adherens junctions and causes massive dysplasia of the brain. Furthermore, RhoA -deficient neural progenitor cells exhibit accelerated proliferation, reduction of cell- cycle exit, and increased expression of downstream target genes of the hedgehog pathway. Consequently, both lines of conditional RhoA -deficient embryos exhibit expansion of neural progenitor cells and exencephaly-like protrusions. These results demonstrate a critical role of RhoA in the maintenance of apical adherens junctions and the regulation of neural progenitor proliferation in the developing mammalian brain.

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Section: Discussionmentioning

confidence: 99%

Section: Cns Development | Cell Adhesionmentioning

confidence: 99%

Loss of RhoA in neural progenitor cells causes the disruption of adherens junctions and hyperproliferation

Katayama

Meléndez

Baumann

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

101

138

View full text Add to dashboard Cite

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“…It has been proposed that self-renewal and differentiation of early neural progenitor cells is regulated by symmetric and asymmetric cell divisions [1][2][3][4]. Inheritance of the apical plasma membrane and its junctional complexes is associated with neural progenitor proliferation, whereas lack of its inheritance leads to lineage restriction and differentiation [1].…”

Section: Introductionmentioning

confidence: 99%

The Apical Polarity Determinant Crumbs 2 Is a Novel Regulator of ESC-Derived Neural Progenitors

Boroviak

Rashbass

2011

Stem Cells

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ESCs undergoing neural differentiation in vitro display an intrinsic heterogeneity with a large subset of the cells forming polarized neural rosettes that maintain the neural progenitor microenvironment. This heterogeneity is not only necessary for normal development but also causes substantial technical challenges for practical applications. Here, we report a novel regulator of early neural progenitors, the apical polarity protein Crb2 (Crumbs homologue 2). Employing monolayer differentiation of mouse ESCs to model neurogenesis in vitro, we find that Crb2 is upregulated with Sox1 and Musashi at the onset of neuroepithelial specification and localizes to the apical side of neural rosettes. Stable Crb2-knockdown (KD) lines die at the onset of neural specification and fail to stabilize several apical polarity proteins. However, these cells are able to proliferate under selfrenewing conditions and can be differentiated into mesodermal and endodermal lineages. Conversely, Crb2 overexpression during neural differentiation results in elevated levels of other apical polarity proteins and increases proliferation. Additionally, sustained overexpression of Crb2 reduces terminal differentiation into TuJ1-positive neurons. Furthermore, we demonstrate that Crb2 overexpression under selfrenewing conditions increases glycogen synthase kinase (GSK)-3b inhibition, correlating with an increase in clonogenicity. To confirm the importance of GSK-3b inhibition downstream of Crb2, we show that Crb2-KD cells can be forced into neural lineages by blocking GSK-3b function and supplementing Epidermal Growth Factor (EGF) and basic Fibroblast Growth Factor (bFGF). Thus, this is the first demonstration that a member of the Crumbs family is essential for survival and differentiation of ESC-derived neural progenitors.

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“…Cross talk exists between the cell cycle machinery and differentiation pathways to ensure that progenitor populations are maintained and that differentiation is induced at the time of terminal mitosis (McConnell and Kaznowski, 1991;Nguyen et al, 2006;Farkas and Huttner, 2008;Frank and Tsai, 2009). Despite the importance of the precise coordination of these events, the mechanisms by which the cell cycle machinery integrates with differentiation signals remain poorly understood.…”

Section: Introductionmentioning

confidence: 99%

The Rb/E2F Pathway Modulates Neurogenesis through Direct Regulation of the Dlx1/Dlx2 Bigene Cluster

Ghanem¹,

Andrusiak²,

Svoboda³

et al. 2012

Journal of Neuroscience

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During brain morphogenesis, the mechanisms through which the cell cycle machinery integrates with differentiation signals remain elusive. Here we show that the Rb/E2F pathway regulates key aspects of differentiation and migration through direct control of the Dlx1 and Dlx2 homeodomain proteins, required for interneuron specification. Rb deficiency results in a dramatic reduction of Dlx1 and Dlx2 gene expression manifested by loss of interneuron subtypes and severe migration defects in the mouse brain. The Rb/E2F pathway modulates Dlx1/Dlx2 regulation through direct interaction with a Dlx forebrain-specific enhancer, I12b, and the Dlx1/Dlx2 proximal promoter regions, through repressor E2F sites both in vitro and in vivo. In the absence of Rb, we demonstrate that repressor E2Fs inhibit Dlx transcription at the Dlx1/Dlx2 promoters and Dlx1/2-I12b enhancer to suppress differentiation. Our findings support a model whereby the cell cycle machinery not only controls cell division but also modulates neuronal differentiation and migration through direct regulation of the Dlx1/Dlx2 bigene cluster during embryonic development.

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The cell biology of neural stem and progenitor cells and its significance for their proliferation versus differentiation during mammalian brain development

Cited by 220 publications

References 62 publications

Loss of RhoA in neural progenitor cells causes the disruption of adherens junctions and hyperproliferation

Loss of RhoA in neural progenitor cells causes the disruption of adherens junctions and hyperproliferation

The Apical Polarity Determinant Crumbs 2 Is a Novel Regulator of ESC-Derived Neural Progenitors

The Rb/E2F Pathway Modulates Neurogenesis through Direct Regulation of the Dlx1/Dlx2 Bigene Cluster

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