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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    • "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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    • "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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    • "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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