Editorial: Reelin-Related Neurological Disorders and Animal Models

Homozygous, loss-of-function mutations in the mouse Reelin gene cause a severe neurological phenotype known as reeler. These mutant mice exhibit marked cerebellar hypoplasia, dyslamination of cortical and hippocampal cellular layers, and malposition of specific neuronal populations in the brain stem and spinal cord. Similarly, homozygous mutations in the very conserved human REELIN gene cause a severe neurodevelopmental disorder known as lissencephaly with cerebellar hypoplasia (LCH). These structural defects underscore the essential role that Reelin plays in the control of neuronal migration in the prenatal and early postnatal brain. However, the Reelin protein also affects synapse formation and function in the postnatal and adult brain, and this function is reflected in the manifestation of behavioral and cognitive deficits in heterozygous reeler mice that express reduced levels of Reelin and do not exhibit overt brain structural defects. A reduction in REELIN expression is also found in human patients affected by neuropsychiatric disorders, including autism, schizophrenia, and depression. How does a deficit in REELIN expression contribute to these diseases? In order to understand the potential role of Reelin dysfunction in neuropsychiatric disorders we need to gain a deeper understanding of the molecular mechanisms by which this protein controls all aspects of brain development and function. This Research Topic is a collection of reviews that summarize and interpret many recent findings in the Reelin field. The Topic also includes original research articles that provide novel information on Reelin expression and function in different regions of the central nervous system. Reelin is a large glycoprotein that is secreted by different neuronal populations at different stages of brain development. Shortly after its discovery, it became clear that Reelin is subject to proteolytic cleavage after secretion, resulting in the generation of multiple extracellular protein fragments. The functional significance of this process was not well understood. In recent years, several studies have shed some light on this event, identifying specific cleavage sites, and addressing the consequence of proteolytic cleavage for Reelin biological function. Ranaivoson et al. review structural aspects of Reelin as a ligand, discussing its proteolytic fragments, and the binding of uncleaved and cleaved products to known cell surface receptors. Lussier et al. further review Reelin proteolytic cleavage and its potential role in modulating synapse function in the normal adult brain or in neurodegeneration. Two reviews then discuss in depth molecular aspects of Reelin signal transduction that are initiated by distinct Reelin protein isoforms. Lee and D'Arcangelo …