Control of Neuronal Migration and Aggregation by Reelin Signaling in the Developing Cerebral Cortex - PubMed (original) (raw)

Review

Control of Neuronal Migration and Aggregation by Reelin Signaling in the Developing Cerebral Cortex

Yuki Hirota et al. Front Cell Dev Biol. 2017.

Abstract

The mammalian cerebral neocortex has a well-organized laminar structure, achieved by the highly coordinated control of neuronal migration. During cortical development, excitatory neurons born near the lateral ventricle migrate radially to reach their final positions to form the cortical plate. During this process, dynamic changes are observed in the morphologies and migration modes, including multipolar migration, locomotion, and terminal translocation, of the newborn neurons. Disruption of these migration processes can result in neuronal disorders such as lissencephaly and periventricular heterotopia. The extracellular protein, Reelin, mainly secreted by the Cajal-Retzius neurons in the marginal zone during development, plays a crucial role in the neuronal migration and neocortical lamination. Reelin signaling, which exerts essential roles in the formation of the layered neocortex, is triggered by the binding of Reelin to its receptors, ApoER2 and VLDLR, followed by phosphorylation of the Dab1 adaptor protein. Accumulating evidence suggests that Reelin signaling controls multiple steps of neuronal migration, including the transition from multipolar to bipolar neurons, terminal translocation, and termination of migration beneath the marginal zone. In addition, it has been shown that ectopically expressed Reelin can cause neuronal aggregation via an N-cadherin-mediated manner. This review attempts to summarize our knowledge of the roles played by Reelin in neuronal migration and the underlying mechanisms.

Keywords: Reelin signaling; neocortical development; neuronal migration.

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Figures

Figure 1

Figure 1

Schema of the migratory modes of the excitatory neurons during neocortical development and molecular mechanisms downstream of Reelin signaling that control neuronal migration. In the early developmental stages (Left), neurons generated from the radial glial cells undergo somal translocation, in which they extend processes to the MZ and shorten their leading processes to move their cell bodies to their final positions just beneath the MZ. During somal translocation, nectin-mediated activation of N-cadherin promotes cellular interaction between the neurons and the CR cells. In addition, n-cofilin expressed in the migrating neurons promotes anchoring of the leading processes to the MZ. N-cadherin also stabilizes the leading processes of the migrating neurons elongating into the MZ. In the later stages (Right), the neurons sequentially change their migratory modes. First, in the MAZ, they exhibit multipolar migration, in which they extend and retract multiple processes dynamically while their somata wander. Multipolar cells then transform into a bipolar morphology. Reelin signaling controls the multipolar-to-bipolar transition via the Rap1/N-cadherin pathway. N-cofilin-mediated regulation of the actin cytoskeleton is involved in the radial migration of the neurons in the IZ. Bipolar neurons show locomotion, in which they directionally migrate in the IZ and CP using radial glial fibers as the scaffold. Finally, when they arrive at the outermost region of the CP, they switch to the terminal translocation mode, in which the somata move rapidly in a radial glia-independent manner to just beneath the MZ to complete migration. N-cadherin promotes neuronal accumulation in the PCZ. Reelin signaling activates integrin α5β1 in the migrating neurons, causing them to adhere to the fibronectin localized in the MZ. LIMK1/n-cofilin and integrin α5β1/fibronectin promote anchoring of the leading processes to the MZ.

Figure 2

Figure 2

Ectopic expression of Reelin causes neuronal aggregation in vivo. In the developing neocortex (Left), Reelin (red) is mainly secreted from the CR cells in the MZ, into which the migrating neurons extend their apical leading processes. The PCZ is densely occupied by neuronal somata (gray). In neuronal aggregation induced by ectopically expressed Reelin (Right), the leading processes of the migrating neurons assemble in the Reelin-rich central region, and the cell bodies are aligned in the PCZ-like peripheral region (gray). In both cases, the migrating neurons exhibit an “inside-out” cell arrangement in which the late-born cells (green) pass by the early-born neurons (magenta).

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