Proneural Transcription Factors Regulate Different Steps of Cortical Neuron Migration through Rnd-Mediated Inhibition of RhoA Signaling

Abstract

SummaryLittle 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. Interestingly, these divergent functions directly result from the distinct subcellular distributions of the two Rnd proteins. Because Rnd proteins also regulate progenitor divisions and neurite outgrowth, we propose that proneural factors, through spatiotemporal regulation of Rnd proteins, integrate the process of neuronal migration with other events in the neurogenic program.

Rnd3 as a Novel Target to Ameliorate Microvascular Leakage

“…Using a combination of cell culture, ex vivo, and in vivo approaches, we have identified evidence supporting that Rnd3 has barrier‐protective properties under certain conditions, such as following acute inflammatory challenge. The involvement of Rnd3 in the control of endothelial barrier function adds to a growing list of recently described functions ascribed to Rnd family proteins, including Ca 2+ homeostasis in the heart,53 regulation of Notch1 signaling,54 control of cell cycle progression,55, 56, 57 development of the central nervous system,58, 59, 60 control of cell motility and metastatic potential of certain cancers,29, 61, 62, 63, 64 and a potential role in cardioprotection against heart failure 65. In addition, we provide novel evidence that delivery of Rnd3 protein can serve as a potential therapeutic tool to ameliorate microvascular hyperpermeability caused by tissue injury.…”

Speed control for neuronal migration in the postnatal brain by Gmip-mediated local inactivation of RhoA

“…59) was kindly provided by Dr Michiyuki Matsuda, Kyoto University. FRET-based imaging for RhoA activity in KD cells was performed essentially as described previously 31 . The three-dimensional Matrigel culture used for the time-lapse imaging of migrating new neurons was performed as described in the previous section.…”

“…Gmip has a Rho-GAP activity 28 and regulates cell morphology in cultured fibroblasts by deactivating RhoA. Although several studies suggested that RhoA is crucial for neuronal migration in the embryonic cerebral cortex [31][32][33][34][35] , neither the spatio-temporal activation pattern of RhoA signalling in the migrating OB neurons nor its regulatory mechanisms has been demonstrated. To study the expression of RhoA, we immunostained cultured new neurons dissociated from postnatal mouse V-SVZ tissues.…”

Connexin 43 controls the multipolar phase of neuronal migration to the cerebral cortex

“…The newly generated neurons usually undergo transient multipolar transformation before assuming radial migration (8, 10). Based on these observations, it has been proposed that many developmental disorders, such as periventricular nodular heterotopia, subcortical band heterotopia, and doublecortex syndrome are related to migration abnormalities including its multipolar stage at SVZ/VZ (11-13).The molecular mechanisms controlling directly and/or indirectly the multipolar stage of neuronal migration have just begun to be recognized (7,(14)(15)(16)(17). For example, knockdown or inactivation of Filamin A or LIS1 accumulated the multipolar neurons in the VZ and SVZ, whereas knockdown or inactivation of Doublecortin (DCX) accumulated these cells in the IZ (18,19).…”

“…The molecular mechanisms controlling directly and/or indirectly the multipolar stage of neuronal migration have just begun to be recognized (7,(14)(15)(16)(17). For example, knockdown or inactivation of Filamin A or LIS1 accumulated the multipolar neurons in the VZ and SVZ, whereas knockdown or inactivation of Doublecortin (DCX) accumulated these cells in the IZ (18,19).…”