The Apical Complex Couples Cell Fate and Cell Survival to Cerebral Cortical Development

Kim, Seonhee; Lehtinen, Maria K.; Sessa, Alessandro; Zappaterra, Mauro; Cho, Seo Hee; Gonzalez, Dilenny M.; Boggan, Brigid; Austin, Christina A.; Wijnholds, Jan; Gambello, Michael J.; Malicki, Jarema; LaMantia, Anthony S.; Broccoli, Vania; Walsh, Christopher A.

doi:10.1016/j.neuron.2010.03.019

Cited by 109 publications

(140 citation statements)

References 76 publications

(97 reference statements)

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“…Apical polarity proteins are fundamentally important for neural development, that is, Par3 and Par6 localize apically and promote proliferation of neural progenitors in the developing mouse cerebral cortex [16], overexpression and mislocalization of aPKCf increases neural progenitor numbers [15], and very recently it has been shown that loss of Pals1, notably a member of the Crumbs complex, resulted in massive cell death during cortical development [19]. This is similar to our Crb2-KD phenotype.…”

Section: Crb2 Is Required For Stabilization Of Apical Polarity Proteinssupporting

confidence: 84%

“…GSK-3b is a core component of Wnt/b-catenin signaling [10] and a key regulator of neurogenesis [11][12][13]. Although several components of the Par complex have been reported to play a pivotal role in neurogenesis [14][15][16][17][18], and a recent study shows that Pals1 is important for cell survival in the cerebral cortex [19], almost nothing is known about the function of the Crumbs proteins in mammalian neurogenesis.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Crb2 Is Required For Stabilization Of Apical Polarity Proteinssupporting

confidence: 84%

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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“…1B′,C′, red arrow), which confirms deletion from the cerebellum and validates the specificity of the Pals1 probe. In accordance with known neuroepithelium expression patterns (Ishiuchi et al, 2009;Kim et al, 2010), Pals1 proteins also localized to the apical surface in the URL and VZ of WT (Fig. 1D,F).…”

Section: Pals1 Is Expressed In Progenitors During Cerebellar Developmentsupporting

confidence: 84%

“…Polarity complexes include evolutionarily conserved apical complex proteins, such as the Crb complex (comprising Crbs, Pals1, Patj), the Par complex (Par3, Par6, aPKC) and basal complex proteins, such as the Scribble complex (Scribbles, Lgl, Dlg) (Assémat et al, 2008;Pieczynski and Margolis, 2011;Tepass, 2012). Previous studies have demonstrated that apical complex proteins are necessary for self-renewal of neural progenitor cells (Bultje et al, 2009;Costa et al, 2008;Kim et al, 2010), neuronal migration (Famulski et al, 2010;Solecki et al, 2006), axon determination (Chen et al, 2013;Shi et al, 2003), dendrite development (Tanabe et al, 2010), tissue polarity and neuron survival (Kim et al, 2010). However, there is little information about the function of apical complex proteins in the regulation of proliferation and differentiation of CGNPs, which lack typical apical-basal polarity.…”

Section: Introductionmentioning

confidence: 99%

Apical complex protein Pals1 is required to maintain cerebellar progenitor cells in a proliferative state

et al. 2015

Self Cite

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Through their biased localization and function within the cell, polarity complex proteins are necessary to establish the cellular asymmetry required for tissue organization. Well-characterized germinal zones, mitogenic signals and cell types make the cerebellum an excellent model for addressing the crucial function of polarity complex proteins in the generation and organization of neural tissues. Deletion of the apical polarity complex protein Pals1 in the developing cerebellum results in a remarkably undersized cerebellum with disrupted layers in poorly formed folia and strikingly reduced granule cell production. We demonstrate that Pals1 is not only essential for cerebellum organogenesis, but also for preventing premature differentiation and thus maintaining progenitor pools in cerebellar germinal zones, including cerebellar granule neuron precursors in the external granule layer. In the Pals1 mouse mutants, the expression of genes that regulate the cell cycle was diminished, correlating with the loss of the proliferating cell population of germinal zones. Furthermore, enhanced Shh signaling through activated Smo cannot overcome impaired cerebellar cell generation, arguing for an epistatic role of Pals1 in proliferation capacity. Our study identifies Pals1 as a novel intrinsic factor that regulates the generation of cerebellar cells and Pals1 deficiency as a potential inhibitor of overactive mitogenic signaling.

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“…First, apically localized cell junctions and the apicobasal polarity complexes have been implicated in the asymmetric cell division of NPCs (Farkas and Huttner, 2008). Mutations or experimental manipulations that affect the apical complex or the apical-basal polarity of NPCs often result in neurogenic abnormalities, such as precocious neuronal differentiation (Bultje et al, 2009;Cappello et al, 2006;Costa et al, 2008;Kim et al, 2010;Yokota et al, 2009). As the disruption of AJs may affect the apicobasal polarity of NPCs, the neurogenic phenotypes described here were potentially caused by this cell-autonomous mechanism.…”

Section: Roles Of the Cell-cell Junction In Neurogenesismentioning

confidence: 93%

Cadherin-based adhesions in the apical endfoot are required for active Notch signaling to control neurogenesis in vertebrates

et al. 2014

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The development of the vertebrate brain requires an exquisite balance between proliferation and differentiation of neural progenitors. Notch signaling plays a pivotal role in regulating this balance, yet the interaction between signaling and receiving cells remains poorly understood. We have found that numerous nascent neurons and/or intermediate neurogenic progenitors expressing the ligand of Notch retain apical endfeet transiently at the ventricular lumen that form adherens junctions (AJs) with the endfeet of progenitors. Forced detachment of the apical endfeet of those differentiating cells by disrupting AJs resulted in precocious neurogenesis that was preceded by the downregulation of Notch signaling. Both Notch1 and its ligand Dll1 are distributed around AJs in the apical endfeet, and these proteins physically interact with ZO-1, a constituent of the AJ. Furthermore, live imaging of a fluorescently tagged Notch1 demonstrated its trafficking from the apical endfoot to the nucleus upon cleavage. Our results identified the apical endfoot as the central site of active Notch signaling to securely prohibit inappropriate differentiation of neural progenitors.

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The Apical Complex Couples Cell Fate and Cell Survival to Cerebral Cortical Development

Cited by 109 publications

References 76 publications

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

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

Apical complex protein Pals1 is required to maintain cerebellar progenitor cells in a proliferative state

Cadherin-based adhesions in the apical endfoot are required for active Notch signaling to control neurogenesis in vertebrates

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