New Insights into Reelin-Mediated Signaling Pathways

Abstract

Reelin, a multifunctional extracellular protein that is important for mammalian brain development and function, is secreted by different cell types in the prenatal or postnatal brain. The spatiotemporal regulation of Reelin expression and distribution during development relates to its multifaceted function in the brain. Prenatally Reelin controls neuronal radial migration and proper positioning in cortical layers, whereas postnatally Reelin promotes neuronal maturation, synaptic formation and plasticity. The molecular mechanisms underlying the distinct biological functions of Reelin during and after brain development involve unique and overlapping signaling pathways that are activated following Reelin binding to its cell surface receptors. Distinct Reelin ligand isoforms, such as the full-length protein or fragments generated by proteolytic cleavage differentially affect the activity of downstream signaling pathways. In this review, we discuss recent advances in our understanding of the signaling transduction pathways activated by Reelin that regulate different aspects of brain development and function. A core signaling machinery, including ApoER2/VLDLR receptors, Src/Fyn kinases, and the adaptor protein Dab1, participates in all known aspects of Reelin biology. However, distinct downstream mechanisms, such as the Crk/Rap1 pathway and cell adhesion molecules, play crucial roles in the control of neuronal migration, whereas the PI3K/Akt/mTOR pathway appears to be more important for dendrite and spine development. Finally, the NMDA receptor (NMDAR) and an unidentified receptor contribute to the activation of the MEK/Erk1/2 pathway leading to the upregulation of genes involved in synaptic plasticity and learning. This knowledge may provide new insight into neurodevelopmental or neurodegenerative disorders that are associated with Reelin dysfunction.

Keywords: brain development; dendrites; neuronal migration; signal transduction; synaptogenesis.

Figure 1

Schematic structure of the Reelin protein and its cleavage fragments. Reelin contains a signal peptide (S), an F-spondin-like domain (SL), eight consecutive Reelin repeats (R) each harboring an epidermal growth factor (EGF)-like motif that separates two subdomains (A and B), and a positively charged carboxy-terminal region (CTR). The full-length protein is cleaved by extracellular metalloproteases at specific sites (arrows), an N-terminal (Nt) site within R3 and a C-terminal site between R6 and R7. These two cleavage events generate three large fragments, an N-terminal (Nt), a central (C) and a C terminal (Ct) fragment. An additional cleavage event (empty head arrow) occurs within the CTR (WC) and generates a small carboxy-terminal peptide.

Figure 2

Reelin signaling mechanisms in brain development and function. Reelin is secreted as a full-length protein that contains three large cleavable domains, an Nt, a C, and a Ct domain. The central domain binds to ApoER2 and VLDLR receptors, which internalize the ligand and transduce the Reelin signal by activating Src/Fyn kinases that phosphorylate the adaptor protein Dab1. Downstream of this canonical pathway, distinct signaling cascades regulate specific biologic activities at different times during brain development. (A) Prenatally, Reelin controls neuronal migration and cortical layer formation through the Crk/C3G/Rap1 pathway. This signaling cascade regulates the function of cell adhesion molecules, including nectin3, N-Cadherin, and Integrin α5β1, which facilitate somal translocation and cellular layer formation. (B) During early postnatal development, the Crk adaptor proteins and the PI3K-Akt-mTOR pathway contribute to Reelin activity by promoting protein translation, dendrite outgrowth and spine development. (C) In the late postnatal and adult brain Reelin affects synaptic function and plasticity. This activity is mediated in part by ApoER2, which interacts with the NMDAR through PSD-95, causing Ca²⁺ influx and the activation of CamKII. An unknown receptor also mediates the activation of the MEK-Erk1/2 pathway by Src/Fyn kinases. Together these signaling pathways promote synaptic activity and plasticity through the induction of immediate-early genes involved in learning and memory such as those containing LRN enhancers.