신경아세포 이동과정에서 Ezrin-Radixin-Moesin 단백질의 기능

Abstract

During the brain development, cell migration is a critical step for the correct positioning of specific neuronal populations, which is necessary for the efficient neural network formation. As new neurons are continuously added to the limited areas of adult brain, newly produced neuroblasts are required to migrate to their final destination. For instance, new neurons are continuously produced from the subventricular zone (SVZ) of the lateral ventricles in the adult brain, and they migrated via rostral migratory stream (RMS) to the olfactory bulb (OB). This type of cell migration in the RMS has unique features that cells migrate in a chain-like homophilic formation while passing through the physical/chemical barriers formed by glial cells (glial tube). Following brain injury, endogenous neuronal progenitors escape from their normal migratory RMS track and migrate toward the injury sites. Therefore, the signals and mechanisms controlling RMS migration in the adult brain may be distinct from those in the embryonic brain, but the precise mechanisms regulating RMS migration remain to be further explored. To identify novel mechanisms involved in the RMS migration, firstly I screened genes that are dominantly expressed in the RMS (where migrating neuroblasts are enriched), compared to the OB (where mature neurons localized) by a genome-wide microarray analysis. Based on subsequent bioinformatical and in situ hybridization analyses, I isolated at least 6 novel candidate genes: Ezrin, Radixin, Moesin, Gjb1, Gje1, and Phactr4. Among these candidates, the role of Ezrin-Radixin-Moesin (ERM) proteins in the RMS migration was further investigated. ERM proteins are key mediators that link signals from extracellular membrane to intracellular actin cytoskeleton. Migrating neuroblasts in the RMS express at least two members of ERM, Ezrin and Radixin. Furthermore, as a sign of functional activation, phosphorylation of ERM was also observed in migrating neuroblasts, suggesting that ERM proteins are involved in neuroblast migration in the RMS. When the functions of ERM in the neuroblasts are blocked by infection of retrovirus expressing a dominant-negative-ERM (DN-ERM), the infected neuroblasts lost their typical bipolar morphology of migrating cells and exhibited a marked impairment of migration in vitro and in vivo. These results raise the possibility that ERM functions are required for the maintenance of cell polarity which is required for the efficient RMS migration. Migration of neural progenitor cells toward the injured site is one of the earliest responses after neuronal damage, and it is known that SDF1 released from microglia recruits neuroblast to the injury site via the CXCR4 receptor activation. Next, I investigated whether ERM activation is also required for the injury-induced neuroblast migration. Interestingly, phosphorylation of ERM was dramatically increased in the RMS neuroblasts after cryogenic traumatic brain injury. Pharmacological inhibition of SDF1-CXCR4 signaling efficiently blocked the injury-induced ERM phosphorylation, and direct treatment of SDF1 in cultured neuroblasts enhanced ERM phosphorylation, suggesting that injury-induced SDF1 promoted ERM phosphorylation. Furthermore, directed migration of neuroblasts to the injured cortex was blunted either by treatment with SDF1 inhibitor or by infection of neuroblasts with DN-ERM retrovirus, suggesting that ERM activation may mediate the injury-induced neuroblast migration. Collectively, these results suggest that ERM activation is an essential step for the directional migration of neuroblasts in the RMS and the cortical re-routing after brain injury.