Reln, encoding the large extracellular protein Reelin, plays several critical roles in brain development and function. It is involved in regulating neuronal migration and positioning in the developing brain, and sustains functionality in the adult brain. Reelin activates neuronal signal transduction pathways related to synaptic plasticity, dendritic morphology, and cognitive function in the adult brain [1,2].

In humans, biallelic RELN variants are associated with a recessive lissencephaly variant with cerebellar hypoplasia, similar to the homozygous mouse mutant. Monoallelic RELN variants are associated with frontotemporal or temporal-predominant lissencephaly variant, epilepsy, autism, and probably schizophrenia, with incomplete penetrance and variable expressivity. Heterozygous missense variants can cause a severe reduction in overall RELN secretion, suggesting a dominant-negative effect [1]. Mice with exonic RELN deletion showed impaired visual discrimination learning and reversal learning in touchscreen operant tasks, indicating its role in cognitive function [2].

In conclusion, Reln is essential for brain development and function, especially in processes related to neuronal migration, synaptic plasticity, and cognitive function. Studies on RELN-related neurodevelopmental disorders and cognitive impairments in mouse models have deepened our understanding of the gene's role in these processes, potentially providing insights for the treatment of related diseases [1,2].