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• W2031845013 abstract "Neurogenesis is integrated with neuronal migration to ensure proper development of the cerebral cortex. Reporting in Neuron, Pacary et al., 2011Pacary E. Heng J. Azzarelli R. Riou P. Castro D. Lebel-Potter M. Parras C. Bell D.M. Ridley A.J. Parsons M. Guillemot F. Neuron. 2011; 69: 1069-1084Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar demonstrate that proneural factors activate atypical Rho GTPases Rnd2 and Rnd3 in newborn cortical neurons, leading to compartmentalized modulation of RhoA signaling and differential control of neuronal migration stages. Neurogenesis is integrated with neuronal migration to ensure proper development of the cerebral cortex. Reporting in Neuron, Pacary et al., 2011Pacary E. Heng J. Azzarelli R. Riou P. Castro D. Lebel-Potter M. Parras C. Bell D.M. Ridley A.J. Parsons M. Guillemot F. Neuron. 2011; 69: 1069-1084Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar demonstrate that proneural factors activate atypical Rho GTPases Rnd2 and Rnd3 in newborn cortical neurons, leading to compartmentalized modulation of RhoA signaling and differential control of neuronal migration stages. The coordinated and sequential unfolding of neurogenesis, neuronal migration, and postmigratory neuronal differentiation is essential to the functional cellular organization of the cerebral cortex. Neurons, derived from radial progenitors, transit through a multipolar stage prior to assuming a bipolar morphology and undergoing radial glial-guided migration to the cortical plate (Kriegstein and Noctor, 2004Kriegstein A.R. Noctor S.C. Trends Neurosci. 2004; 27: 392-399Abstract Full Text Full Text PDF PubMed Scopus (487) Google Scholar, LoTurco and Bai, 2006LoTurco J.J. Bai J. Trends Neurosci. 2006; 29: 407-413Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar, Tabata et al., 2009Tabata H. Kanatani S. Nakajima K. Cereb. Cortex. 2009; 19: 2092-2105Crossref PubMed Scopus (90) Google Scholar) (Figure 1A ). The integration of neurogenesis with neuronal migration is essential to deploy the appropriate number and types of neurons to the developing neocortex. Work from Pacary et al., 2011Pacary E. Heng J. Azzarelli R. Riou P. Castro D. Lebel-Potter M. Parras C. Bell D.M. Ridley A.J. Parsons M. Guillemot F. Neuron. 2011; 69: 1069-1084Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar in a recent issue of Neuron shed new light on the orchestration of this integration and how early neurogenic programs might modulate distinct migration phases of their neuronal progeny. Complementing previous findings that the proneural gene Neurog2 induces the expression of Rnd2, a member of the Rnd family of GTP-binding proteins, in newborn cortical neurons to promote their migration (Heng et al., 2008Heng J.I. Nguyen L. Castro D.S. Zimmer C. Wildner H. Armant O. Skowronska-Krawczyk D. Bedogni F. Matter J.M. Hevner R. Guillemot F. Nature. 2008; 455: 114-118Crossref PubMed Scopus (201) Google Scholar), Pacary et al., 2011Pacary E. Heng J. Azzarelli R. Riou P. Castro D. Lebel-Potter M. Parras C. Bell D.M. Ridley A.J. Parsons M. Guillemot F. Neuron. 2011; 69: 1069-1084Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar identify another proneural transcription factor, Ascl1, as a direct inducer of the Rnd family member Rnd3 in new neurons. Rnd2 and -3, however, do not functionally compensate for each other during neuronal migration, indicating that they play distinct roles in this process (Figure 1). Rnd3 knockdown in migrating neurons resulted in enlarged leading processes with numerous branches and increased centrosome-nucleus distance, indicative of disrupted nuclear-centrosome coupling during bipolar neuronal movement. In contrast, Rnd2-deficient neurons failed to leave the intermediate zone (IZ) and displayed long processes and multipolar morphology, suggesting that Rnd2 is critical for the multipolar to bipolar transition that occurs in the IZ. To identify the molecular pathways involved in Rnd-regulated steps of neuronal migration, the authors examined RhoA activity in migrating neurons. RhoA FRET analysis detected increased RhoA activity in both Rnd2- and -3-deficient migrating neurons, whereas knockdown of RhoA rescued migratory defects associated with Rnd2 or Rnd3 loss. The inhibitory effect of Rnd3 on RhoA activity depends on its interactions with Rho GTPase activating protein, p190RhoGap, whereas Rnd2's RhoA inhibitory activity does not. Further, although both Rnd2 and -3 can regulate actin dynamics in migrating neurons, only Rnd3 promotes neuronal migration by inhibiting RhoA-mediated actin polymerization and remodeling. The authors found that the distinct cellular localization of Rnd2 and -3 and the resultant modulation of RhoA activity in different cell compartments underlie the difference in their effects. Rnd3 specifically associates with the plasma membrane of neuronal cell soma and processes. Indeed, a mutant allele of Rnd3 resistant to membrane dissociation rescued Rnd3-deficient neuronal migration, whereas the loss of membrane associate abolished this effect. The modulation of RhoA activity at the neuronal cell membrane may thus distinguish Rnd3's effect on neuronal migration from that of Rnd2, which mainly associates with early endosomes in the cell soma. Together with the previous work on Rnd2, these findings provide compelling evidence that the progenitor-derived proneural factor induction of Rnd2 and -3 proteins in distinct compartments in neuronal progeny leads to the differential modulation of RhoA activity and actin remodeling in distinct neuronal compartments, thus enabling newborn neurons to step through the migratory process necessary to reach their final destinations in cerebral cortex (Figure 1). The modulation of RhoA in distinct cell compartments appears to be an essential element in mediating the effects of Rnd2 and -3 in migrating neurons. To further refine this model and extend the understanding of how dynamic RhoA signaling controls the different steps of neuronal migration, it will be important to monitor RhoA activity with high temporal and spatial fidelity in the cell (possibly through tracking RhoA with biosensors using high resolution time-lapse live imaging; Machacek et al., 2009Machacek M. Hodgson L. Welch C. Elliott H. Pertz O. Nalbant P. Abell A. Johnson G.L. Hahn K.M. Danuser G. Nature. 2009; 461: 99-103Crossref PubMed Scopus (653) Google Scholar), as well as directly test the sufficiency of subcellular RhoA activation for stages in neuronal migration using localized photoactivatable RhoA. Studies with photoactivatable analogs of Rac suggest that changes in Rac activity in one cell can be sensed by surrounding cells and used to polarize and alter the directionality of clusters of cells (Wang et al., 2010Wang X. He L. Wu Y.I. Hahn K.M. Montell D.J. Nat. Cell Biol. 2010; 12: 591-597Crossref PubMed Scopus (229) Google Scholar). Whether similar mechanisms are also at work as a result of Rnd induced changes in RhoA activity in isochronic cohorts of neurons as they transition through different steps of migration will be intriguing to test. Further, considering the importance of subcellular localization of Rnd2 and -3 in effecting their functional diversity, it will be critical to determine how Rnd2 and -3 are targeted to select cellular compartments during both migration and postmigratory differentiation. The divergent effects of Rnd2 and -3 on F-actin polymerization in different neuronal compartments suggest that Rnds may generate polarized F-actin dynamics in migrating neurons, and this may underlie the motility and polarity differences evident in multipolar and bipolar neurons. Similarly, polarized endocytosis is also critical for directed neuronal cell movement (Kawauchi et al., 2010Kawauchi T. Sekine K. Shikanai M. Chihama K. Tomita K. Kubo K. Nakajima K. Nabeshima Y. Hoshino M. Neuron. 2010; 67: 588-602Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar). In cortical neurons, Rnd2 and Rnd3 are localized to overlapping, yet distinct, pools of endosomes, suggesting that both factors may also play a role in the regulation of endocytosis and membrane trafficking. Thus, it will be important to define whether Rnds are also involved in the polarized cytoskeletal dynamics or the endocytosis/trafficking of cell-surface receptors or adhesion molecules that are necessary to facilitate radially oriented neuronal migration. Neuronal migration defects in humans lead to significant brain malformations, such as periventricular heterotopia, lissencephaly, and cortical band heterotopia. Mutations in cytoskeletal regulators filaminA (FlnA), Lis1, and doublecortin (DCX), respectively, cause each of these brain malformations and also potently regulate the multipolar to bipolar transition (reviewed in LoTurco and Bai, 2006LoTurco J.J. Bai J. Trends Neurosci. 2006; 29: 407-413Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar). A recent study also suggested that multipolar neurons differentiate into layer II/III pyramidal neurons and that the multipolar stage might facilitate the initial axonal protrusion of these neurons (Tabata et al., 2009Tabata H. Kanatani S. Nakajima K. Cereb. Cortex. 2009; 19: 2092-2105Crossref PubMed Scopus (90) Google Scholar). Together, these observations indicate that the multipolar-to-bipolar transition of migrating neurons is likely to have a significant role in the development of normal organization of human cerebral cortex, although it remains to be established if transition through a multipolar stage helps trigger the differentiation program of any particular neuronal subtype. Deciphering how and if Rnd2 and -3 interacts with or regulates any of the genes associated with human neuronal migration defects will further highlight the relative significance of the proneural factors-Rnd2/3-RhoA/cytoskelton pathway in cerebral cortical development. Proneural Transcription Factors Regulate Different Steps of Cortical Neuron Migration through Rnd-Mediated Inhibition of RhoA SignalingPacary et al.NeuronMarch 24, 2011In BriefLittle is known of the intracellular machinery that controls the motility of newborn neurons. We have previously shown that the proneural protein Neurog2 promotes the migration of nascent cortical neurons by inducing the expression of the atypical Rho GTPase Rnd2. Here, we show that another proneural factor, Ascl1, promotes neuronal migration in the cortex through direct regulation of a second Rnd family member, Rnd3. Both Rnd2 and Rnd3 promote neuronal migration by inhibiting RhoA signaling, but they control distinct steps of the migratory process, multipolar to bipolar transition in the intermediate zone and locomotion in the cortical plate, respectively. Full-Text PDF Open Access" @default.
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• W2031845013 title "Rnd-ing up RhoA Activity to Link Neurogenesis with Steps in Neuronal Migration" @default.
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