The Rho-GTPase cdc42 regulates neural progenitor fate at the apical surface

Cappello, Silvia; Attardo, Alessio; Wu, Xunwei; Iwasato, Takuji; Itohara, Shigeyoshi; Wilsch‐Bräuninger, Michaela; Eilken, Hanna M.; Rieger, Michael A.; Schroeder, Timm; Huttner, Wieland B.; Brakebusch, Cord; Götz, Magdalena

doi:10.1038/nn1744

Cited by 354 publications

(419 citation statements)

References 49 publications

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“…Many polarity proteins involved in apico-basal polarity of neuroepithelial progenitors in the neocortex, e.g., those in the apical polarity complex aPKC/Par3/Par6, and Cdc42 [53][54][55], are also required for axon specification [56,57]. The relationship between integrin signaling with some of these polarity proteins has been established in astrocyte polarization and migration [58] -the interaction of integrins with ECM at the newly formed cell front leads to the activation and polarized recruitment of Cdc42, which in turn recruits and activates the cytoplasmic mPar6/PKCζ complex, which further modifies MT cytoskeleton.…”

Section: Laminin/itgb1 Signaling and Neuronal Polarity Proteinsmentioning

confidence: 99%

Laminin/β1 integrin signal triggers axon formation by promoting microtubule assembly and stabilization

et al. 2012

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Axon specification during neuronal polarization is closely associated with increased microtubule stabilization in one of the neurites of unpolarized neuron, but how this increased microtubule stability is achieved is unclear. Here, we show that extracellular matrix (ECM) component laminin promotes neuronal polarization via regulating directional microtubule assembly through β1 integrin (Itgb1). Contact with laminin coated on culture substrate or polystyrene beads was sufficient for axon specification of undifferentiated neurites in cultured hippocampal neurons and cortical slices. Active Itgb1 was found to be concentrated in laminin-contacting neurites. Axon formation was promoted and abolished by enhancing and attenuating Itgb1 signaling, respectively. Interestingly, laminin contact promoted plus-end microtubule assembly in a manner that required Itgb1. Moreover, stabilizing microtubules partially prevented polarization defects caused by Itgb1 downregulation. Finally, genetic ablation of Itgb1 in dorsal telencephalic progenitors caused deficits in axon development of cortical pyramidal neurons. Thus, laminin/Itgb1 signaling plays an instructive role in axon initiation and growth, both in vitro and in vivo, through the regulation of microtubule assembly. This study has established a linkage between an extrinsic factor and intrinsic cytoskeletal dynamics during neuronal polarization.

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Section: Laminin/itgb1 Signaling and Neuronal Polarity Proteinsmentioning

confidence: 99%

Laminin/β1 integrin signal triggers axon formation by promoting microtubule assembly and stabilization

et al. 2012

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“…Cdc42-GTP binds to the Par6-aPKC dimer, resulting in aPKC activation [48]. Both Cdc42 and aPKC are associated with neurogenesis [15,18,49,50].…”

Section: A Model For Apical Polarity Protein Signaling In Neuroepithementioning

confidence: 99%

“…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%

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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“…These have been shown to have essential roles in cell fate decisions related to cell cycle exit, cell-type choice, and laminar positioning (Malicki, 2004;Gotz and Huttner, 2005). Furthermore, apical junctionassociated signaling molecules such as atypical protein kinase C (aPKC) and Cdc42, via their affects on overall cell polarity, are essential for normal interkinetic nuclear migration (Cappello et al, 2006;Cui et al, 2007). At the basal surface, distinct signaling complexes exist including those associated with focal adhesions (Li and Sakaguchi, 2002;Wozniak et al, 2004).…”

Section: Maintenance Of Apical-basal Polaritymentioning

confidence: 99%

Nuclear migration during retinal development

2008

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In this review we focus on the mechanisms, regulation, and cellular consequences of nuclear migration in the developing retina. In the nervous system, nuclear migration is prominent during both proliferative and post-mitotic phases of development. Interkinetic nuclear migration is the process where the nucleus oscillates from the apical to basal surfaces in proliferative neuroepithelia. Proliferative nuclear movement occurs in step with the cell cycle, with M-phase being confined to the apical surface and G1-, S-, and G2-phases occurring at more basal locations. Later, following cell cycle exit, some neuron precursors migrate by nuclear translocation. In this mode of cellular migration, nuclear movement is the driving force for motility. Following discussion of the key components and important regulators for each of these processes, we present an emerging model where interkinetic nuclear migration functions to distinguish cell fates among retinal neuroepithelia. Keywordsinterkinetic nuclear migration; nuclear translocation; nucleokinesis; neurogenesis; dynein; cell cycle; cell behavior OverviewNeuronal development is regulated by a complex array of intrinsic and extrinsic signals that act on progenitor neuroepithelial cells to ensure the correct cell type is generated in the right numbers and at the appropriate time of development (Donovan et al., 2005;Cayouette et al., 2006). In addition, multiple signaling cues are integrated in post-mitotic neuronal precursors to facilitate directed cell migration and correct laminar positioning (Malicki et al., 2004). This spatial and temporal regulation of neuronal cell-type fate commitment and histogenesis is dependent on the regulation of the mitotic cell cycle, and in particular at the level of cell cycle exit (Ohnuma and Harris, 2003). Recent data suggest that nuclear migration is a critical process for several aspects of neuronal development, including that of the neural retina. The focus of this review is on interkinetic nuclear migration and nuclear translocation during retinogenesis, although much of what we know is from observations in other regions of the developing nervous system. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript Interkinetic nuclear migrationInterkinetic nuclear migration is the proliferative cell behavior where the nuclei of neuroepithelial cells migrate in an apical-basal manner and in phase with the cell cycle (Frade 2002). Neuroepithelial cell divisions are confined to apical locations while S-phase occu...

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The Rho-GTPase cdc42 regulates neural progenitor fate at the apical surface

Cited by 354 publications

References 49 publications

Laminin/β1 integrin signal triggers axon formation by promoting microtubule assembly and stabilization

Laminin/β1 integrin signal triggers axon formation by promoting microtubule assembly and stabilization

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

Nuclear migration during retinal development

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