Visium Spatial Gene Expression of embryonic mouse brain at embryonic day 15.5

Lissencephaly is a congenital neurodevelopmental disorder characterized by a complete loss of or simplified convolutions on the brain surface. It has been reported to result from genetic variants that lead to neuronal migration defects during cortical development. However, genetic causes inof nearly one-fifth of lissencephaly patients remain unidentified. Using trio whole exome sequencing (WES), we identified a de novo BAIAP2 variant p.Arg29Trp from a Taiwanese lissencephaly patient with a posterior more severe than anterior (P > A) gradient, implicating BAIAP2 as a potential lissencephaly gene. Using spatial gene expression profiling, in situ hybridization, and immunofluorescence staining in the developing cortex, we found that Baiap2 was expressed in the cortical plate (CP) and intermediate zone (IZ) in an anterior low to posterior high gradient. To examine the potential roles of BAIAP2 in the pathogenesis of lissencephaly, we used in utero electroporation to explore the effects of the Baiap2 variant in the developing mouse cortex. We found that Baiap2 knockdown caused abnormalities in the migration, morphogenesis and differentiation of developing neurons. Expression of the p.Arg29Trp variant failed to rescue the migration defect, suggesting a loss-of-function effect of this variant. Mechanistically, we found that the variant interfered with the ability of BAIAP2 to localize to the cell membrane. These results suggest that BAIAP2 functions in the cytoskeleton, cell morphogenesis and migration, which are important for cortical development and the pathogenesis of human lissencephaly in humans.