MODELING REELIN FUNCTIONS IN HUMAN CEREBRAL ORGANOIDS

Reelin is a key regulator in early and late cortical development through the control of neuronal migration and involvement in synapse formation late into adulthood. Its expression levels seem to be significantly altered in several neurodevelopmental and neuropsychiatric diseases such as schizophrenia, epilepsy, autism, affective disorders, lissencephaly and Alzheimer’s disease, with some rare gene variants also likely being causally involved in these diseases. Yet recently, a thorough case study identified a variant of the RELN gene as the most probable factor to have delayed the onset of the cognitive impairment in a patient with familial Alzheimer’s disease by about 3 decades compared to the average of predisposing PSEN1-E280A mutation carriers [1]. The effects of this reelin variant have been studied partially in murine neuronal cell culture and isogenic mice, similar to most research findings about reelin function and dysfunction, which have been gained primarily from rodents. Due to its relevance for human disease and neuroplasticity, we aim to establish human cerebral organoids as models to further study reelin’s function and the impact of specific variants on cortical structure, development and potential for neural regeneration. As a first step towards that goal, we are generating undirected cerebral organoids from RELN-WT, RELN-KO and RELN-COLBOS (the putative gain-of-function variant) CRISPR/Cas9-modified human induced pluripotent stem cells (hiPSCs) as decribed per Lancaster et al. [doi: 10.1038/nature12517.].