How does Reelin signaling regulate the neuronal cytoskeleton during migration?

Abstract

Neuronal migration is an essential step in the formation of laminated brain structures. In the developing cerebral cortex, pyramidal neurons migrate toward the Reelin-containing marginal zone. Reelin is an extracellular matrix protein synthesized by Cajal-Retzius cells. In this review, we summarize our recent results and hypotheses on how Reelin might regulate neuronal migration by acting on the actin and microtubule cytoskeleton. By binding to ApoER2 receptors on the migrating neurons, Reelin induces stabilization of the leading processes extending toward the marginal zone, which involves Dab1 phosphorylation, adhesion molecule expression, cofilin phosphorylation and inhibition of tau phosphorylation. By binding to VLDLR and integrin receptors, Reelin interacts with Lis1 and induces nuclear translocation, accompanied by the ubiquitination of phosphorylated Dab1. Eventually Reelin induces clustering of its receptors resulting in the endocytosis of a Reelin/receptor complex (particularly VLDLR). The resulting decrease in Reelin contributes to neuronal arrest at the marginal zone.

Keywords: Dab1 phosphorylation; cofilin phosphorylation; endocytosis; nuclear translocation; radial neuronal migration; receptor clustering; reelin receptors; stabilization of cytoskeleton.

Figure 1.

Schematic view of neurons at E14.5–18.5 migrating radially along radial fibers toward the marginal zone.

Figure 2.

A summary diagram of Reelin signaling pathways involving cell membrane receptors, the major lipid products of PI3K: PIs and intracellular downstream molecules.