Reelin

Reelin is a large secreted extracellular matrix glycoprotein encoded by the RELN gene. It was identified for its crucial role in establishing the proper laminated organization of the developing cerebral cortex, hippocampus, and cerebellum, as first demonstrated by the abnormal cortical layering observed in reeler mice.

The reelin protein is synthesized as a large precursor that is secreted into the extracellular space and then proteolytically processed into smaller fragments. Its expression is developmentally regulated: high in the marginal zone of the developing cortex by Cajal-Retzius cells, and later detectable in various interneuron populations within the cortex and hippocampus and in cerebellar cells. The protein contains multiple extracellular repeats and domains that mediate interactions with receptors and other extracellular matrix components.

Reelin signals by binding to the lipoprotein receptors ApoER2 and VLDLR on the surface of neurons. This receptor engagement leads to phosphorylation of the cytoplasmic adaptor protein Dab1 by Src family kinases, triggering a downstream cascade that influences cytoskeletal dynamics and neuronal migration. In the developing cortex, reelin signaling regulates the stop and positioning of migrating neurons, promoting proper lamination and cortical plate formation. It also contributes to neuronal polarization and dendritic development.

In the adult brain, reelin continues to influence synaptic function and plasticity, including modulation of NMDA receptor signaling and long-term potentiation in hippocampal circuits. Reduced reelin expression or disrupted signaling has been associated with neuropsychiatric and neurodevelopmental conditions, including schizophrenia and autism spectrum disorders, while classic loss-of-function RELN mutations can cause severe cortical and cerebellar malformations such as lissencephaly with cerebellar hypoplasia.