Canonical and Non-canonical Reelin Signaling

Abstract

Reelin is a large secreted glycoprotein that is essential for correct neuronal positioning during neurodevelopment and is important for synaptic plasticity in the mature brain. Moreover, Reelin is expressed in many extraneuronal tissues; yet the roles of peripheral Reelin are largely unknown. In the brain, many of Reelin’s functions are mediated by a molecular signaling cascade that involves two lipoprotein receptors, apolipoprotein E receptor-2 (Apoer2) and very low density-lipoprotein receptor (Vldlr), the neuronal phosphoprotein Disabled-1 (Dab1), and members of the Src family of protein tyrosine kinases as crucial elements. This core signaling pathway in turn modulates the activity of adaptor proteins and downstream protein kinase cascades, many of which target the neuronal cytoskeleton. However, additional Reelin-binding receptors have been postulated or described, either as coreceptors that are essential for the activation of the “canonical” Reelin signaling cascade involving Apoer2/Vldlr and Dab1, or as receptors that activate alternative or additional signaling pathways. Here we will give an overview of canonical and alternative Reelin signaling pathways, molecular mechanisms involved, and their potential physiological roles in the context of different biological settings.

Genetics and mechanisms leading to human cortical malformations

“…Reln canonical pathways, involving the activation of the ApoER2/Vldlr/Dab1 signaling, appear to mediate many Reln-dependent functions during pre-and postnatal brain development and function [160]. However, SFKs that are central in Reln signal transduction allow the activation of two distinct branches: PI3K-Akt-and MEK-Erk1/2-dependent signaling cascades, which converge on downstream effectors, as was reported in cortical neurons in vitro [161].…”

“…This is phosphorylated by Src family kinases (SFK) at different sites, which initiates a signaling cascade to induce neuronal migration [160], including Crk/Rap1 signaling affecting cell adhesion, and phosphatidylinositol-3 kinase PI3K/Akt and mTOR signaling [161,162]. Dab1 is then ubiquitinated leading to proteasome degradation, suggesting that this sequence of activation and shutoff may be crucial for the execution of multiple steps in neuronal migration [162].…”

APP Protein Family Signaling at the Synapse: Insights from Intracellular APP-Binding Proteins

“…In the adult brain, reelin signaling through ApoER2 alters the activity of postsynaptic glutamate receptors in hippocampal slices, affecting LTP and synaptic plasticity (Weeber et al, 2002; Beffert et al, 2005). These events are also dependent on tyrosine phosphorylation of the Dab1 adaptor protein and the subsequent recruitment of Src family kinases to phosphorylated Dab1, known as the canonical reelin signaling pathway (reviewed in Bock and May, 2016). In the adult hippocampus, Dab1 regulates synaptic plasticity (Trotter et al, 2013).…”

Physiological significance of proteolytic processing of Reelin revealed by cleavage-resistant Reelin knock-in mice

“…Reelin is a large secreted glycoprotein that regulates many important events in mammalian brain development [1][2][3] . It is also involved in synaptic plasticity and the modulation of higher brain functions 1,[4][5][6][7][8] . At the cellular level, Reelin induces the clustering of apolipoprotein E receptor 2 (ApoER2) and very-low-density lipoprotein receptor (VLDLR), which is the prerequisite for the phosphorylation of the cytosolic adaptor protein Dab1 [9][10][11] .…”