Regulation of Cortical Neuron Migration by the Reelin Signaling Pathway

Reeler is a mutant mouse with defects in layered structures of the central nervous system, such as the cerebral cortex, hippocampus, and cerebellum, and has been extensively examined for more than half a century. The full-length cDNA for the responsible gene for reeler, reelin, was serendipitously identified, revealing that Reelin encodes a large secreted protein. So far, two Reelin receptors, apolipoprotein E receptor 2 and very low-density lipoprotein receptor, and the cytoplasmic adaptor protein Disabled homolog 1 (Dab1) have been shown to be essential for Reelin signaling. Although a number of downstream cascades of Dab1 have also been reported using various experimental systems, the physiological functions of Reelin in vivo remain controversial. Here, we review recent advances in the understanding of the Reelin-Dab1 signaling pathway in the developing cerebral cortex. neurotransmitter glutamate, and inhibitory interneurons, which secrete gamma-aminobutyric-acid (GABA) as their primary neurotransmitter. Since their birthplaces are different from the sites where they eventually reside, these neurons must migrate to their final destinations to exert their functions correctly. Glutamatergic neurons are produced in the ventricular zone (VZ) or subventricular zone (SVZ) of the cerebral cortex (pallium) and migrate radially toward the pial surface [1, 2], whereas inhibitory interneurons are produced in the ganglionic eminences in the ventral telencephalon and migrate tangentially toward the cerebral cortex [2, 3]. From analyses of mutant mice, knockout mice, and human hereditary diseases, key molecules that regulate the orchestrated migration of neurons have been gradually identified [4, 5]. Among them, Reelin is an essential molecule for the proper positioning of cortical neurons [6]. Although the functions of Reelin have been extensively examined, how Reelin regulates the positioning of neurons remains unclear. In this review, we provide an overview of the neuroanatomical abnormalities of the cerebral cortex in reeler mutant mice, summarize the current understanding of the Reelin signaling pathway, and discuss Reelin functions in vivo.