Neurogenin 2 controls cortical neuron migration through regulation of Rnd2. Nature

Division of Molecular Neurobiology, National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
Nature (Impact Factor: 41.46). 10/2008; 455(7209):114-8. DOI: 10.1038/nature07198
Source: PubMed


Motility is a universal property of newly generated neurons. How cell migration is coordinately regulated with other aspects of neuron production is not well understood. Here we show that the proneural protein neurogenin 2 (Neurog2), which controls neurogenesis in the embryonic cerebral cortex, directly induces the expression of the small GTP-binding protein Rnd2 (ref. 3) in newly generated mouse cortical neurons before they initiate migration. Rnd2 silencing leads to a defect in radial migration of cortical neurons similar to that observed when the Neurog2 gene is deleted. Remarkably, restoring Rnd2 expression in Neurog2-mutant neurons is sufficient to rescue their ability to migrate. Our results identify Rnd2 as a novel essential regulator of neuronal migration in the cerebral cortex and demonstrate that Rnd2 is a major effector of Neurog2 function in the promotion of migration. Thus, a proneural protein controls the complex cellular behaviour of cell migration through a remarkably direct pathway involving the transcriptional activation of a small GTP-binding protein.

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Available from: Dorota Skowronska-Krawczyk, May 07, 2015
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    • "Neurog2 enhances neuronal migration, independently of its proneural activity, but by activating Rho-GAP expression via C-terminal tyrosine (Y241) phosphorylation that leads to inhibition of RhoA activity (Hand et al., 2005). Furthermore, Neurog2 promotes neuronal migration by upregulating the expression of Rnd2, an inhibitor of RhoA signaling, independently of Y241 phosphorylation (Heng et al., 2008). Thus, Neurog2 can promote neuronal migration by inhibiting RhoA activity via two independent mechanisms: Y241 phosphorylation and Rnd2 induction. "
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    Neuron 04/2014; 82(1):9-23. DOI:10.1016/j.neuron.2014.03.018 · 15.05 Impact Factor
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    • "This highlights genes involved in the control of the duration and mode of cell division (symmetric/asymmetric) as important factors for cerebral expansion in evolution (Huttner and Kosodo, 2005; Rakic, 2009). Finally, the manner by which a larger number of postmitotic cells migrate radially from the proliferative VZ/SVZ to become deployed in the cortical plate as a relatively thin sheet is a biological necessity that enables cortical expansion during evolution (Heng et al., 2008; Noctor et al., 2001; Rakic, 1988, 1995; Takahashi et al., 1999; Yu et al., 2009). More recently, electroporation and transgenic technologies show intermixing of the ontogenetic columns in the SVA that is necessary for the formation of functional columns with different compositions and constellations of cell types (Figure 1A; Torii et al., 2009). "
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    Neuron 10/2013; 80(3):633-47. DOI:10.1016/j.neuron.2013.10.045 · 15.05 Impact Factor
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    • "814 RP58 Controls Neuron Migration Through Rnd2 • Heng et al. temporally, in the developing cortical landscape (Supplementary Fig. 7A,B). In addition, recent findings have revealed that RP58, NeuroD1, and Rnd2 are direct target genes of Neurog2 (Schuurmans et al. 2004; Gohlke et al. 2008; Heng et al. 2008), hence RP58 may form part of a signaling network through which Neurog2 specifies the migratory properties of newborn cortical projection neurons within the embryonic cerebral cortex. Indeed, RP58 may reciprocally regulate the expression of Neurog2 and Neurod1 as neurons mature within the cortex (Xiang et al. 2011; Ohtaka-Maruyama et al. 2013), and so it will be important to delineate the precise role for RP58 in both the generic properties of cortical neuron differentiation, as well as within distinct subprograms that control aspects of their differentiation , such as cell migration. "
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    ABSTRACT: The zinc finger transcription factor RP58 (also known as ZNF238) regulates neurogenesis of the mouse neocortex and cerebellum (Okado et al. 2009; Xiang et al. 2011; Baubet et al. 2012; Ohtaka-Maruyama et al. 2013), but its mechanism of action remains unclear. In this study, we report a cell-autonomous function for RP58 during the differentiation of embryonic cortical projection neurons via its activities as a transcriptional repressor. Disruption of RP58 expression alters the differentiation of immature neurons and impairs their migration and positioning within the mouse cerebral cortex. Loss of RP58 within the embryonic cortex also leads to elevated mRNA for Rnd2, a member of the Rnd family of atypical RhoA-like GTPase proteins important for cortical neuron migration (Heng et al. 2008). Mechanistically, RP58 represses transcription of Rnd2 via binding to a 3′-regulatory enhancer in a sequence-specific fashion. Using reporter assays, we found that RP58 repression of Rnd2 is competed by proneural basic helix–loop–helix transcriptional activators. Finally, our rescue experiments revealed that negative regulation of Rnd2 by RP58 was important for cortical cell migration in vivo. Taken together, these studies demonstrate that RP58 is a key player in the transcriptional control of cell migration in the developing cerebral cortex.
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