Heng, J.I. et al. Neurogenin 2 controls cortical neuron migration through regulation of Rnd2. Nature 455, 114-118

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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    • "Previous studies have reported that RP58 is a DNA-binding transcriptional repressor (Aoki et al. 1998; Xiang et al. 2011), which raised the possibility that RP58 could directly control Rnd2 expression through a putative regulatory enhancer within Rnd2. We had previously characterized an enhancer element (known as the Rnd2 3′enhancer), which was important for regulating Rnd2 expression in the cortex (Heng et al. 2008), and was also found to comprise an RP58-binding site (Quandt et al. 1995) (data not shown). We performed ChIP experiments with embryonic E14.5 cortical tissue and confirmed that RP58 binds to this enhancer element in vivo (Fig. 3D). "
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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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