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Rnd-Ing up Rhoa Activity to Link Neurogenesis with Steps in Neuronal Migration

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Rnd-Ing up Rhoa Activity to Link Neurogenesis with Steps in Neuronal Migration Developmental Cell Previews Rnd-ing up RhoA Activity to Link Neurogenesis with Steps in Neuronal Migration Jingjun Li1 and E.S. Anton1,* 1UNC Neuroscience Center and the Department of Cell and Molecular Physiology, The University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA *Correspondence: [email protected] DOI 10.1016/j.devcel.2011.04.001 Neurogenesis is integrated with neuronal migration to ensure proper development of the cerebral cortex. Reporting in Neuron, Pacary et al. (2011) 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 zone (IZ) and displayed long processes Rnd2 and -3 proteins in distinct compart- of neurogenesis, neuronal migration, and and multipolar morphology, suggesting ments in neuronal progeny leads to the postmigratory neuronal differentiation is that Rnd2 is critical for the multipolar to differential modulation of RhoA activity essential to the functional cellular organiza- bipolar transition that occurs in the IZ. and actin remodeling in distinct neuronal tion of the cerebral cortex. Neurons, To identify the molecular pathways compartments, thus enabling newborn derived from radial progenitors, transit involved in Rnd-regulated steps of neurons to step through the migratory through a multipolar stage prior to neuronal migration, the authors examined process necessary to reach their final assuming a bipolar morphology and under- RhoA activity in migrating neurons. RhoA destinations in cerebral cortex (Figure 1). going radial glial-guided migration to the FRET analysis detected increased RhoA The modulation of RhoA in distinct cell cortical plate (Kriegstein and Noctor, activity in both Rnd2- and -3-deficient compartments appears to be an essential 2004; LoTurco and Bai, 2006; Tabata migrating neurons, whereas knockdown element in mediating the effects of Rnd2 et al., 2009)(Figure 1A). The integration of of RhoA rescued migratory defects associ- and -3 in migrating neurons. To further neurogenesis with neuronal migration is ated with Rnd2 or Rnd3 loss. The inhibitory refine this model and extend the under- essential to deploy the appropriate number effect of Rnd3 on RhoA activity depends standing of how dynamic RhoA signaling and types of neurons to the developing on its interactions with Rho GTPase acti- controls the different steps of neuronal neocortex. Work from Pacary et al. (2011) vating protein, p190RhoGap, whereas migration, it will be important to monitor in a recent issue of Neuron shed new light Rnd2’s RhoA inhibitory activity does not. RhoA activity with high temporal and on the orchestration of this integration and Further, although both Rnd2 and -3 can spatial fidelity in the cell (possibly through how early neurogenic programs might regulate actin dynamics in migrating tracking RhoA with biosensors using high modulate distinct migration phases of their neurons, only Rnd3 promotes neuronal resolution time-lapse live imaging; neuronal progeny. migration by inhibiting RhoA-mediated Machacek et al., 2009), as well as directly Complementing previous findings that actin polymerization and remodeling. The test the sufficiency of subcellular RhoA the proneural gene Neurog2 induces the authors found that the distinct cellular activation for stages in neuronal migration expression of Rnd2, a member of the Rnd localization of Rnd2 and -3 and the resul- using localized photoactivatable RhoA. family of GTP-binding proteins, in newborn tant modulation of RhoA activity in different Studies with photoactivatable analogs of cortical neurons to promote their migration cell compartments underlie the difference Rac suggest that changes in Rac activity (Heng et al., 2008), Pacary et al. (2011) in their effects. Rnd3 specifically associ- in one cell can be sensed by surrounding identify another proneural transcription ates with the plasma membrane of cells and used to polarize and alter factor, Ascl1, as a direct inducer of the neuronal cell soma and processes. the directionality of clusters of cells Rnd family member Rnd3 in new neurons. Indeed, a mutant allele of Rnd3 resistant (Wang et al., 2010). Whether similar mech- Rnd2 and -3, however, do not functionally to membrane dissociation rescued Rnd3- anisms are also at work as a result of Rnd compensate for each other during deficient neuronal migration, whereas the induced changes in RhoA activity in iso- neuronal migration, indicating that they loss of membrane associate abolished chronic cohorts of neurons as they transi- play distinct roles in this process this effect. The modulation of RhoA activity tion through different steps of migration (Figure 1). Rnd3 knockdown in migrating at the neuronal cell membrane may thus will be intriguing to test. Further, consid- neurons resulted in enlarged leading distinguish Rnd3’s effect on neuronal ering the importance of subcellular locali- processes with numerous branches and migration from that of Rnd2, which mainly zation of Rnd2 and -3 in effecting their increased centrosome-nucleus distance, associates with early endosomes in the functional diversity, it will be critical to indicative of disrupted nuclear-centro- cell soma. Together with the previous determine how Rnd2 and -3 are targeted some coupling during bipolar neuronal work on Rnd2, these findings provide to select cellular compartments during movement. In contrast, Rnd2-deficient compelling evidence that the progenitor- both migration and postmigratory neurons failed to leave the intermediate derived proneural factor induction of differentiation. Developmental Cell 20, April 19, 2011 ª2011 Elsevier Inc. 409 Developmental Cell Previews regulate the multipolar to bipolar transi- tion (reviewed in LoTurco and Bai, 2006). 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., 2009). 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 partic- ular neuronal subtype. Deciphering how and if Rnd2 and -3 interacts with or regu- lates 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 Figure 1. Rnd2 and -3 Control Different Steps of Cortical Neuronal Migration (A) New neurons generated from radial progenitors undergo a transient multipolar migratory state in the development. SVZ and IZ prior to adopting a bipolar morphology and radial glial-guided migration to the cortical plate where they differentiate. (B) Cellular localization of atypical Rho GTPases Rnd2 (orange) and Rnd3 (blue) in migrating neurons. Pro- REFERENCES neural factors, Ascl1 and Neurog2, induce Rnd2 and Rnd3 expression in migrating neurons, respectively. Rnd3 is localized to plasma membrane and early and recycling endosomes, whereas Rnd2 is mostly local- ized to early endosomes. Heng, J.I., Nguyen, L., Castro, D.S., Zimmer, C., (C) Rnd3 loss-of-function results in enlarged leading processes with multiple branches, increased Wildner, H., Armant, O., Skowronska-Krawczyk, nucleus-centrosome distance, enhanced RhoA activity in plasma membrane (data not shown), accumu- D., Bedogni, F., Matter, J.M., Hevner, R., and Guillemot, F. (2008). Nature 455, 114–118. lation of F-actin in neuronal processes, and disrupted migration of bipolar neurons. In contrast, Rnd2 loss- of-function leads to an overall increase in RhoA activity, enhanced F-actin polymerization in cell soma and Kawauchi, T., Sekine, K., Shikanai, M., Chihama, processes, elongated processes, and inhibition of the multipolar-to-bipolar transition of migrating K., Tomita, K., Kubo, K., Nakajima, K., Nabeshima, neurons. VZ, ventricular zone; SVZ, subventricular zone; IZ, intermediate zone; CP, cortical plate. Y., and Hoshino, M. (2010). Neuron 67, 588–602. Kriegstein, A.R., and Noctor, S.C. (2004). Trends The divergent effects of Rnd2 and -3 on trafficking. Thus, it will be important to Neurosci. 27, 392–399. F-actin polymerization in different define whether Rnds are also involved LoTurco, J.J., and Bai, J. (2006). Trends Neurosci. neuronal compartments suggest that in the polarized cytoskeletal dynamics 29, 407–413. Rnds may generate polarized F-actin or the endocytosis/trafficking of cell- dynamics in migrating neurons, and this surface receptors or adhesion molecules Machacek, M., Hodgson, L., Welch, C., Elliott, H., Pertz, O., Nalbant, P., Abell, A., Johnson, G.L., may underlie the motility and polarity that are necessary to facilitate radially Hahn, K.M., and Danuser, G. (2009). Nature 461, differences evident in multipolar and oriented neuronal migration. 99–103. bipolar neurons. Similarly, polarized endo- Neuronal migration defects in humans Pacary, E., Heng, J., Azzarelli, R., Riou, P., Castro, cytosis is also critical for directed neuronal lead to significant brain malformations, D., Lebel-Potter, M., Parras, C., Bell, D.M., Ridley, cell movement (Kawauchi et al., 2010). In such as periventricular heterotopia, lis- A.J., Parsons, M., and Guillemot, F. (2011). Neuron 69, 1069–1084. cortical neurons, Rnd2 and Rnd3 are sencephaly, and cortical band heteroto- localized to overlapping, yet distinct, pia. Mutations in cytoskeletal regulators Tabata, H., Kanatani, S., and Nakajima, K. (2009). pools of endosomes, suggesting that filaminA (FlnA), Lis1, and doublecortin Cereb. Cortex 19, 2092–2105. both factors may also play a role in the (DCX), respectively, cause each of these Wang, X., He, L., Wu, Y.I., Hahn, K.M., and Montell, regulation of endocytosis and membrane brain malformations and also potently D.J. (2010). Nat. Cell Biol. 12, 591–597. 410 Developmental Cell 20, April 19, 2011 ª2011 Elsevier Inc..
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