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

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.

Multiple sevoflurane exposures during pregnancy inhibit neuronal migration by upregulating prostaglandin D2 synthase

“…Neurons subsequently generated in the VZ invade and split the preplate, resulting in the formation of two distinct layers: the marginal zone (MZ) and the deep subplate. Newborn neurons then migrate radially from the VZ, pass through the subplate, and stop beneath the MZ to form the CP (Hirota and Nakajima, 2017). Interestingly, our results demonstrated that following single sevoflurane exposure for 2 h, transfected cells were almost all positioned within the UpCP.…”

Both excitatory and inhibitory neurons transiently form clusters at the outermost region of the developing mammalian cerebral neocortex

“…The first generated cells during corticogenesis form the preplate, which splits and differentiates into the marginal zone (MZ) and the subplate after newly born excitatory neurons start to migrate toward the pial surface (Hirota & Nakajima, ). The neuronal migration is guided by a scaffold called radial fibers of the radial glial cells, which extend to the pial surface (Rakic, , ).…”

“…subplate after newly born excitatory neurons start to migrate toward the pial surface (Hirota & Nakajima, 2017). The neuronal migration is guided by a scaffold called radial fibers of the radial glial cells, which extend to the pial surface (Rakic, 1972(Rakic, , 1988.…”

“…The extracellular protein Reelin, which is secreted mainly by Cajal-Retzius cells within the MZ, is a key molecule causing the proper organization of the cortical layers during neocortical development (Bar et al, 1995;Caviness & Sidman, 1973;D'Arcangelo et al, 1995;Hayashi, Inoue, & Nakajima, 2018;Hirota & Nakajima, 2017;Honda, Kobayashi, Mikoshiba, & Nakajima, 2011;Ogawa et al, 1995). Analyses of the neocortex in the autosomal recessive mutant mouse reeler, which lacks the Reelin molecule, revealed that Reelin is required for the inside-out pattern of neuronal alignment.…”

Fbxo45 binds SPRY motifs in the extracellular domain of N-cadherin and regulates neuron migration during brain development

“…NCad is upregulated on the cell surface at both these stages in response to an extracellular signal, Reelin. Reelin is known to regulate neuron migration and cortical development by stimulating signaling pathways involving Src kinases, Dab1, PI3' kinase, Crk/CrkL, C3G, and the small GTPase, Rap1 (14)(15)(16)(17)(18)(19)(20)(21). Rap1 then regulates NCad surface expression, presumably through Rab GTPase-dependent vesicular trafficking events (9,11,22).…”