Abstract
Reelin is a neuronal glycoprotein secreted by the Cajal-Retzius cells in marginal regions of the cerebral cortex and the hippocampus where it plays important roles in the control of neuronal migration and the formation of cellular layers during brain development. This 3461 residue-long protein is composed of a signal peptide, an F-spondin-like domain, eight Reelin repeats (RR1–8), and a positively charged sequence at the C-terminus. Biochemical data indicate that the central region of Reelin binds to the low-density lipoprotein receptors apolipoprotein E receptor 2 (ApoER2) and the very-low-density lipoprotein receptor (VLDLR), leading to the phosphorylation of the intracellular adaptor protein Dab1. After secretion, Reelin is rapidly degraded in three major fragments, but the functional significance of this degradation is poorly understood. Probably due to its large mass and the complexity of its architecture, the high-resolution, three-dimensional structure of Reelin has never been determined. However, the crystal structures of some of the RRs have been solved, providing important insights into their fold and the interaction with the ApoER2 receptor. This review discusses the current findings on the structure of Reelin and its binding to the ApoER2 and VLDLR receptors, and we discuss some areas where proteomics and structural biology can help understanding Reelin function in brain development and human health.
Highlights
Disruptions of the autosomal recessive Reelin gene were identified two decades ago to be responsible for the reeler phenotype in mice strains originated from Edinburgh and Orleans (D’Arcangelo et al, 1995; Hirotsune et al, 1995)
Reelin has a crucial role in controlling the radial migration of neurons, allowing them to reach their appropriate positions in laminated structures such as the cerebral cortex, the hippocampus or the cerebellum (Lambert de Rouvroit and Goffinet, 1998)
Control of neuronal migration and layer formation is achieved by expression and secretion of Reelin by specific sub-types of cells, namely by Cajal-Retzius cells in marginal regions of the cerebral cortex and the hippocampus (D’Arcangelo et al, 1995; Ogawa et al, 1995; Del Río et al, 1997; Nakajima et al, 1997; Schiffmann et al, 1997; Alcantara et al, 1998), or by granule cell precursors localized in the external granule layer of the embryonic cerebellum (D’Arcangelo et al, 1995; Miyata et al, 1996; Alcantara et al, 1998)
Summary
Disruptions of the autosomal recessive Reelin gene were identified two decades ago to be responsible for the reeler phenotype in mice strains originated from Edinburgh and Orleans (D’Arcangelo et al, 1995; Hirotsune et al, 1995). The involvement of Reelin in layer formation in brain cortical structures was extensively investigated (for an excellent review, see D’Arcangelo, 2014). Control of neuronal migration and layer formation is achieved by expression and secretion of Reelin by specific sub-types of cells, namely by Cajal-Retzius cells in marginal regions of the cerebral cortex and the hippocampus (D’Arcangelo et al, 1995; Ogawa et al, 1995; Del Río et al, 1997; Nakajima et al, 1997; Schiffmann et al, 1997; Alcantara et al, 1998), or by granule cell precursors localized in the external granule layer of the embryonic cerebellum (D’Arcangelo et al, 1995; Miyata et al, 1996; Alcantara et al, 1998). We will discuss the proteolysis of Reelin and we will suggest areas of exploration that, in our opinion, will provide valuable information of the structural and functional mechanisms underlying the biological function of Reelin
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