On-Chip human brain organoids to model development and disease

LIS1 , the first gene to be identified as involved in a neuronal migration disease, is a dosage-sensitive gene whose proper levels are required for multiple aspects
of cortical development. Deletions in LIS1 result in a severe brain malformation, known as lissencephaly, whereas duplications delay brain development. We
modelled one of the hallmarks of lissencephaly, the reduced gyrification using an on-chip device. Live imaging enable to monitor abnormalities in the relative
position of nuclei during inter kinetic nuclear motility as well as reduced apical motion, which could be attributed to the roles of LIS1 in regulation of the
molecular motor cytoplasmic dynein. The reduction in folds was associated with reduced elastic modulus, observed in the lissencephalic organoids.

In addition, we detected a significant change in the differential expression of genes associated with the extracellular matrix (ECM), which was unexpected from
know LIS1 activities. To understand the molecular basis for these phenotypes, we conducted an unbiased multiomics screen using mouse embryonic stem cells
from Lis1 floxed/-, wild type and Lis1 over expression. Our analyses reveal a rich novel LIS1-interactome and multiple changes at the level of RNA and small
RNA. We propose that novel and dynein independent functions of LIS1 affecting gene transcription and protein expression are involved in part of the
phenotypes observed in lissencephalic brains.