Reelin is a secreted modular glycoprotein that exhibits serine protease activity and is crucial for brain development and function (1-3). It is composed of an N-terminal Reelin domain, eight EGF-like Reelin repeats (RR), and a highly basic C-terminal region (4-6). The N-terminal fragment is suggested to mediate dimerization/oligomerization and receptor recognition, the midpiece receptor binding, and the C-terminal fragment receptor signaling and recognition (1, 5, 7-9). Human Reelin is synthesized as a 3460 amino acid (aa) precursor protein with a molecular weight of approximately 410 kDa (4). During processing, it can be cleaved between RR2 and RR3 or between RR6 and RR7, producing a 180 kDa and a 330 kDa peptide, respectively (1, 6, 10). Within shared regions in the central fragment, human Reelin shares 95% aa sequence identity with mouse and rat Reelin.
Reelin is secreted by Cajal-Retzius cells in the embryo (1, 4, 11). In the adult, it is expressed in the subventricular zone, rostral migratory stream, olfactory bulb, and in the CA1, CA3, and dentate gyrus regions of the hippocampus, as well as in cerebellar granule cells, pyramidal cells of the entorhinal cortex, GABA interneurons, and glial cells (1, 6, 12, 13). Reelin utilizes the receptors VLDLR and ApoE R2, which have been suggested to have divergent roles in Reelin-mediated neuronal migration (1, 2, 6, 12). It has also been shown to interact with Integrin alpha 3 beta 1 and APP (1, 6, 14, 15). During cortical plate development, Reelin controls cell-cell interactions critical for proper neuronal migration and positioning (1, 2, 4, 5, 11, 12, 16). In the adult, it plays a role in dendrite growth and maturation, and synapse formation (2, 6, 15). Additionally, Reelin has been shown to modulate synaptic transmission and plasticity by regulating the subunit composition and conductivity of NMDA receptors (2, 6, 17). Mutation of the RELN gene results in lissencephaly with cerebellar hypoplasia (11, 18). In addition, abnormal Reelin expression in the brain has been associated with a variety of cognitive pathological conditions including autism, schizophrenia, bipolar disorder, major depression, and Alzheimer’s disease (1, 6, 11, 13, 19, 20). Peripherally, Reelin is important in the development of neuromuscular junctions. But instead of utilizing the locally expressed ApoE R2 and VLDLR, this function requires the serine protease activity of Reelin (3, 21).
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