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.
Highlights
The aminoterminal phosphotyrosine binding/PTB domain preferentially interacts with the non-phosphorylated NPXY tetra-amino-acid motif (Herz et al, 1988; Chen et al, 1990) in the intracellular tails of transmembrane receptors, including apolipoprotein E receptor 2 (Apoer2) and very low density lipoprotein receptor (Vldlr) and the amyloid precursor protein family members and integrins (Rice et al, 1998; Trommsdorff et al, 1998; Howell et al, 1999b; reviewed in Stolt and Bock, 2006; Yap and Winckler, 2015), and mediates membrane localization by interacting with phosphoinositides (Stolt et al, 2003, 2005; Huang et al, 2005; Xu et al, 2005)
Coprecipitation of Apoer2 and Vldlr after stimulation with the Reelin fragment was not observed in heterologous cells and primary neurons, leaving open the question if Reelin induces its two main receptors to form heteroclusters to a significant extent
Reelin as a Ligand for Amyloid Precursor Protein (APP) The demonstration that the interaction of Reelin with lipoprotein receptors at the adult synapse enhances long-term potentiation through Dab1- and Fyn-dependent phosphorylation of NMDA receptors (Weeber et al, 2002; Beffert et al, 2005; Chen et al, 2005) suggested that Reelin signaling in the adult brain modulates learning and memory performance, which has subsequently been demonstrated in vivo using different experimental approaches including conditional knockout of Reelin, Dab1, or Reelin overexpression in adult mice (Brosda et al, 2011; Rogers et al, 2011, 2013; Trotter et al, 2013; Pujadas et al, 2014; Lane-Donovan et al, 2015; Imai et al, 2016)
Summary
Reelin is best known for its role in the developing mammalian cerebral cortex, where it is secreted by Cajal-Retzius cells in the marginal zone and orchestrates the arrangement of postmitotic cortical neurons in an inside-out manner, meaning that younger neurons are located more superficially than the earlier-born neurons. This process is severely disturbed in the spontaneous mouse mutant reeler, where disruption of the gene encoding Reelin leads to an approximate inversion of the cortical layering. Reelinresponsive cells outside the central nervous system remain mostly elusive, significant amounts of Reelin are detected in plasma and various non-neuronal tissues (Ikeda and Terashima, 1997; Smalheiser et al, 2000; Kobold et al, 2002; Lugli et al, 2003; Botella-Lopez et al, 2008), and functional effects of Reelin on blood cells such as platelets (Tseng et al, 2014), endothelial cells (Ding et al, 2016), or pancreatic cancer cell lines (Sato et al, 2006) have been described
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