Rab GTPases-Dependent Endocytic Pathways Regulate Neuronal Migration and Maturation through N-Cadherin Trafficking

Abstract

Although membrane trafficking pathways are involved in basic cellular functions, the evolutionally expanded number of their related family proteins suggests additional roles for membrane trafficking in higher organisms. Here, we show that several Rab-dependent trafficking pathways differentially participate in neuronal migration, an essential step for the formation of the mammalian-specific six-layered brain structure. In vivo electroporation-mediated suppression of Rab5 or dynamin to block endocytosis caused a severe neuronal migration defect in mouse cerebral cortex. Among many downstream endocytic pathways, suppression of Rab11-dependent recycling pathways exhibited a similar migration disorder, whereas inhibition of Rab7-dependent lysosomal degradation pathways affected only the final phase of neuronal migration and dendrite morphology. Inhibition of Rab5 or Rab11 perturbed the trafficking of N-cadherin, whose suppression also disturbed neuronal migration. Taken together, our findings reveal physiological roles of endocytic pathways, each of which has specific functions in distinct steps of neuronal migration and maturation during mammalian brain formation.

TBC1D24 regulates neuronal migration and maturation through modulation of the ARF6-dependent pathway

“…Several microtubule regulators, such as LIS1, DCX, and CDK5, are essential for the exit of neurons from the multipolar stage (17,22,29), and accumulating evidence now indicates that membrane trafficking can also play a role in the morphological changes underlying radial migration of newborn neurons (30). Notably, Rab5-and Rab11-dependent endocytic pathways control multipolar transition and final CP positioning by regulating the surface expression of N-Cadherin in migrating neurons (30). Our findings also support the physiological importance of monomeric G proteins regulating endocytic pathways in neuronal migration.…”

Rab13-dependent Trafficking of RhoA Is Required for Directional Migration and Angiogenesis

“…6 Similar to other junctional proteins (9,31), the removal of Syx from cell junctions is likely mediated by Rab13-dependent vesicle trafficking, but the recruitment mechanism of Syx to vesicles is unknown. It is unlikely that Syx is recruited to vesicles by its pleckstrin homology domain, because such domains favor binding to phosphatidylinositol 3,4,5-phosphate, whereas the prevalent phosphoinositidephosphate in endosomal membranes is phosphatidylinositol 3-phosphate (38).…”

“…In mouse neurons, directional migration required Rab5-and Rab11-dependent trafficking of the adherens junction protein cadherin (9), similar to epithelial cells in the Drosophila tracheal system (10). The directional migration of border cells during Drosophila oogenesis, guided by EGF and PDGF/VEGF receptor tyrosine kinases, required proteins that mediate receptor tyrosine kinase endocytosis (11) and Rab11 (12).…”

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).…”