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.
Highlights
Reelin is an extracellular glycoprotein that controls diverse aspects of mammalian brain development and function (D’Arcangelo, 2014)
Similar phenotypes are observed in human patients carrying REELIN homozygous mutations, resulting in lissencephaly with cerebellar hypoplasia (Hong et al, 2000)
The best-characterized Reelin receptors are the apolipoprotein E receptor 2 (ApoER2, called LRP8) and the very lowdensity lipoprotein receptor (VLDLR). These proteins belong to the low-density lipoprotein receptor (LDLR) family
Summary
Reelin is an extracellular glycoprotein that controls diverse aspects of mammalian brain development and function (D’Arcangelo, 2014). The most prominent activity of Reelin is the control of neuronal migration and cellular layer formation in the developing brain This is evident from anatomical studies of reeler mutant mice that lack Reelin expression (Lambert de Rouvroit and Goffinet, 1998). In addition to controlling neuronal migration in the prenatal brain, Reelin plays important roles in the postnatal and adult brain, promoting the maturation of dendrites, synaptogenesis, synaptic transmission and plasticity, modulating the formation and function of synaptic circuits This view is supported by animal studies involving heterozygous reeler mice, which model some behavioral dysfunction similar to schizophrenia (Costa et al, 2002), and by recent human genetic studies identifying heterozygous REELIN mutations in lateral temporal epilepsy (Dazzo et al, 2015), and pointing to REELIN as a risk factor in autism (De Rubeis et al, 2014). To foster a better understanding of the mechanisms of development and disease, in this review we focus on recent advances in our knowledge of the signaling transduction pathways that regulate the different biological activities of Reelin in the brain
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