Reelin Signaling Inactivates Cofilin to Stabilize the Cytoskeleton of Migrating Cortical Neurons

Abstract

Neurons are highly polarized cells. They give rise to several dendrites but only one axon. In addition, many neurons show a preferred orientation. For example, pyramidal neurons of the cerebral cortex extend their apical dendrites toward the cortical surface while their axons run in opposite direction toward the white matter. This characteristic orientation reflects the migratory trajectory of a pyramidal cell during cortical development: the leading process (the future apical dendrite) extends toward the marginal zone (MZ) and the trailing process (the future axon) toward the intermediate zone (IZ) while the cells migrate radially to reach their destination in the cortical plate (CP). In this review article, we summarize the function of Reelin, an extracellular matrix protein synthesized by Cajal-Retzius cells in the MZ, in the development of the characteristic orientation of the leading processes running perpendicular to the cortical surface. Reelin promotes migration toward the cortical surface since late-generated cortical neurons in the reeler mutant are unable to reach upper cortical layers. Likewise, Reelin is important for the orientation and maintenance of the leading processes of migrating neurons since they are misoriented in the developing reeler cortex, as are the apical dendrites of pyramidal cells in the mature mutant. Reelin-induced phosphorylation of cofilin, an actin-associated protein, is crucial since pyramidal neurons transfected by in utero electroporation (IUE) with a non-phosphorylatable form of cofilin (cofilinS3A) show severe migration defects reminiscent of those in the reeler mutant. Remarkably, migration of neurons in the cortex of reeler mice was partially rescued by transfecting them with LIM kinase 1 (LIMK1), the kinase that induces phosphorylation of cofilin at serine3, or with a pseudo-phosphorylated cofilin mutant (cofilinS3E). Together these results indicate that Reelin-induced phosphorylation of cofilin is an important component in the orientation and directed migration of cortical neurons and in their correct lamination.

Complement C3 Affects Rac1 Activity in the Developing Brain

“…Rac1 has multiple downstream targets, amongst them it is known to induce the phosphorylation of Cofilin, which promotes actin polymerization (Delorme et al, 2007 ). Furthermore, previous studies have demonstrated that Cofilin is phosphorylated in migrating neurons, downstream to the Reelin pathway, and this activity is important to promote neuronal migration (Chai et al, 2009 ; Frotscher et al, 2017 ). Therefore, E16 brain sections were immunostained with anti-phospho-Cofilin antibodies (Figure 2H ).…”

Formation of the substantia nigra requires Reelin-mediated fast, laterally-directed migration of dopaminergic neurons

“…P-LIMK1 inactivates (phosphorylates) Co1lin1, an actin depolymerizing protein of the ADF/Co1lin family. Reelin-mediated inactivation of Co1lin 1 ultimately leads to the stabilization of the actin cytoskeleton and has been implicated in stabilizing LPs of radially migrating cortical neurons as well as in preventing the aberrant tangential migration of neurons of the autonomous nervous system in the spinal cord Maciver and Hussey (2002) , Krüger et al (2010) , Franco et al (2011) , Chai et al (2009) ; Frotscher et al (2017) . To detect a potential misregulation of these downstream events in absence of Reelin signaling, we performed immunoblotting on E14.5 embryonic ventral midbrain tissue for p-LIMK1/LIMK1 and p-Co1lin1/Co1lin1.…”

Endothelial Dab1 signaling orchestrates neuro-glia-vessel communication in the central nervous system

“…In line with these studies, we found that vascular reelin signaling regulates the secretion of Lama-4 by ECs, which in turn has an impact on radial glia attachment to the pial surface and regulates neuronal migration. Although the regulatory mechanisms of Lama-4 deposition are still largely unknown, it has been reported that Lama-4 is accumulated in focal adhesions (60), which might also be influenced by reelin signaling (61).…”