Reelin: Products
Reelin is a 400 kDa modular glycoprotein that is critical in brain development and function. Reeler mutant mice have a Reelin deficiency and exhibit ataxia, tremors, and impaired motor coordination. Reelin consists of an N-terminal Reelin domain, eight domains that consist of an EGF-like repeat flanked by two subrepeats, and a C-terminal arginine-rich region. Reelin is cleaved into three fragments in vivo by metalloproteases. One (or central) fragment includes domains # 3 - 6 and retains many of the capabilities of the full length molecule.
In addition to being a protease substrate, Reelin itself has serine protease activity. Reelin forms disulfide-linked homodimers and large noncovalently-linked polymers. It utilizes Very Low Density Lipoprotein Receptors (VLDLR) and Apolipoprotein E (ApoE) R2 as receptors, through which it regulates several nervous system functions. Reelin is secreted by Cajal-Retzius cells and cerebellar granule cells during cortical plate development, and is required for proper neuronal migration and positioning.
The N-terminal domain binds integrin alpha-3/beta-1, leading to a disruption of neuronal-glial cell interactions and inhibition of neuronal migration. In the adult hippocampus, cortex, and amygdala, Reelin is required for dendrite growth and maturation, synaptic plasticity, and associative/contextual learning. In this capacity, it regulates the subunit composition of NMDA receptors and modulates NMDA currents, even though it does not interact directly with the receptor.Deficits in ApoE R2, Reelin, and ApoE function have been linked to several cognitive and mood disorders. Peripherally, Reelin is important in the development of neuromuscular junctions. But instead of utilizing the locally expressed ApoE R2 and VLDLR, this involvement requires the serine protease activity of Reelin.
