N-Cadherin regulates radial glial fiber-dependent migration of cortical locomoting neurons

Shikanai, Mima; Nakajima, Kazunori; Kawauchi, Takeshi

doi:10.4161/cib.4.3.14886

Cited by 74 publications

(76 citation statements)

References 28 publications

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“…S5 A-E), whereas overexpression of N-cadherin at a higher concentration (5.0 mg/mL) of the expression plasmid affected neuronal migration (Fig. S5 F-J), as reported previously (34). These results suggest that appropriate regulation, but not persistent increase, of the adhesive forces mediated by N-cadherin is necessary for the cortical neurons to settle in their proper positions eventually.…”

Section: Resultssupporting

confidence: 68%

Reelin transiently promotes N-cadherin–dependent neuronal adhesion during mouse cortical development

Matsunaga

Noda

Murakawa

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Reelin is an essential glycoprotein for the establishment of the highly organized six-layered structure of neurons of the mammalian neocortex. Although the role of Reelin in the control of neuronal migration has been extensively studied at the molecular level, the mechanisms underlying Reelin-dependent neuronal layer organization are not yet fully understood. In this study, we directly showed that Reelin promotes adhesion among dissociated neocortical neurons in culture. The Reelin-mediated neuronal aggregation occurs in an N-cadherin-dependent manner, both in vivo and in vitro. Unexpectedly, however, in a rotation culture of dissociated neocortical cells that gradually reaggregated over time, we found that it was the neural progenitor cells [radial glial cells (RGCs)], rather than the neurons, that tended to form clusters in the presence of Reelin. Mathematical modeling suggested that this clustering of RGCs could be recapitulated if the Reelin-dependent promotion of neuronal adhesion were to occur only transiently. Thus, we directly measured the adhesive force between neurons and N-cadherin by atomic force microscopy, and found that Reelin indeed enhanced the adhesiveness of neurons to N-cadherin; this enhanced adhesiveness began to be observed at 30 min after Reelin stimulation, but declined by 3 h. These results suggest that Reelin transiently (and not persistently) promotes N-cadherin-mediated neuronal aggregation. When N-cadherin and stabilized β-catenin were overexpressed in the migrating neurons, the transfected neurons were abnormally distributed in the superficial region of the neocortex, suggesting that appropriate regulation of N-cadherin-mediated adhesion is important for correct positioning of the neurons during neocortical development.T he mammalian neocortex is highly organized into six neuronal layers. This laminar structure is responsible for the complex motor, sensory, and cognitive functions of the mammalian brain (1). Neuronal migration plays an important role in the establishment of this layered structure. Cortical neurons are generated within the ventricular zone (VZ) or subventricular zone (SVZ), and migrate along radial fibers toward the pial surface. Newly born excitatory neurons migrate radially into the cortical plate (CP) past the neurons born earlier, resulting in a birth date-dependent "inside-out" alignment of the neurons in the CP (2-4).Reelin is a glycoprotein that is secreted by the Cajal-Retzius cells in the marginal zone (MZ) of the cortex during neocortical development (5-7). This glycoprotein is essential for establishment of the aforementioned birth date-dependent layered structure of the neocortex, because the CP neurons show an almost inverted alignment in the neocortex of the Reelindeficient, reeler mice. In addition, neurons born at the same time tend to be distributed broadly and not to form clear layers in the reeler cortex (8, 9). Although extensive studies, including at the molecular level, have been conducted to determine the role of Reelin in neuronal migration i...

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Section: Resultssupporting

confidence: 68%

Reelin transiently promotes N-cadherin–dependent neuronal adhesion during mouse cortical development

Matsunaga

Noda

Murakawa

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…1H), N-cadherin junctions on the surface of neighboring cells serve as a migration track. This N-cadherin junction dependent cell movement is also observed in cortical neuronal locomotion along radial glial fibers (Shikanai et al, 2011). Previous studies have shown that cells exert similar magnitudes of traction forces through N-cadherin junctions as focal adhesions (Ganz et al, 2006), suggesting that N-cadherin junctions are not passive contacts that maintain multicellular integrity, but rather act as an active participant of cell migration.…”

Section: Discussionmentioning

confidence: 75%

N-cadherin-mediated cell–cell adhesion promotes cell migration in a three-dimensional matrix

Shih

Yamada

2012

Journal of Cell Science

114

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SummaryCancer cells that originate from epithelial tissues typically lose epithelial specific cell-cell junctions, but these transformed cells are not devoid of cell-cell adhesion proteins. Using hepatocyte-growth-factor-treated MDCK cells that underwent a complete epithelial-tomesenchymal transition, we analyzed cell-cell adhesion between these highly invasive transformed epithelial cells in a threedimensional (3D) collagen matrix. In a 3D matrix, these transformed cells formed elongated multicellular chains, and migrated faster and more persistently than single cells in isolation. In addition, the cell clusters were enriched with stress-fiber-like actin bundles that provided contractile forces. N-cadherin-knockdown cells failed to form cell-cell junctions or migrate, and the expression of the Ncadherin cytoplasmic or extracellular domain partially rescued the knockdown phenotype. By contrast, the expression of N-cadherina-catenin chimera rescued the knockdown phenotype, but individual cells within the cell clusters were less mobile. Together, our findings suggest that a dynamic N-cadherin and actin linkage is required for efficient 3D collective migration.

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“…We have previously reported that Rab5-dependent endocytosis is required for several steps of neuronal migration, including the radial fiber-dependent locomotion mode Shikanai et al, 2011). However, in a series of these experiments, Rab5-shRNAs were expressed prior to the transition to the locomotion mode.…”

Section: Discussionmentioning

confidence: 99%

Cdk5 and its substrates, Dcx and p27kip1, regulate cytoplasmic dilation formation and nuclear elongation in migrating neurons

et al. 2014

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Neuronal migration is crucial for development of the mammalian-specific six-layered cerebral cortex. Migrating neurons are known to exhibit distinct features; they form a cytoplasmic dilation, a structure specific to migrating neurons, at the proximal region of the leading process, followed by nuclear elongation and forward movement. However, the molecular mechanisms of dilation formation and nuclear elongation remain unclear. Using ex vivo chemical inhibitor experiments, we show here that rottlerin, which is widely used as a specific inhibitor for PKCδ, suppresses the formation of a cytoplasmic dilation and nuclear elongation in cortical migrating neurons. Although our previous study showed that cortical neuronal migration depends on Jnk, another downstream target of rottlerin, Jnk inhibition disturbs only the nuclear elongation and forward movement, but not the dilation formation. We found that an unconventional cyclin-dependent kinase, Cdk5, is a novel downstream target of rottlerin, and that pharmacological or knockdown-mediated inhibition of Cdk5 suppresses both the dilation formation and nuclear elongation. We also show that Cdk5 inhibition perturbs endocytic trafficking as well as microtubule organization, both of which have been shown to be required for dilation formation. Furthermore, knockdown of Dcx, a Cdk5 substrate involved in microtubule organization and membrane trafficking, or p27 kip1 , another Cdk5 substrate involved in actin and microtubule organization, disturbs the dilation formation and nuclear elongation. These data suggest that Cdk5 and its substrates, Dcx and p27 kip1 , characterize migrating neuronspecific features, cytoplasmic dilation formation and nuclear elongation in the mouse cerebral cortex, possibly through the regulation of microtubule organization and an endocytic pathway.

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N-Cadherin regulates radial glial fiber-dependent migration of cortical locomoting neurons

Cited by 74 publications

References 28 publications

Reelin transiently promotes N-cadherin–dependent neuronal adhesion during mouse cortical development

Reelin transiently promotes N-cadherin–dependent neuronal adhesion during mouse cortical development

N-cadherin-mediated cell–cell adhesion promotes cell migration in a three-dimensional matrix

Cdk5 and its substrates, Dcx and p27kip1, regulate cytoplasmic dilation formation and nuclear elongation in migrating neurons

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