Dysregulated Extracellular Matrix and Increased Stiffness in Lissencephaly Brain Organoid Models

LIS1 mutations are known to cause lissencephaly, a neurological disorder characterized by the absence of cerebral cortical convolutions. Here we show that brain organoids with LIS1 mutations exhibit increased expression of extracellular matrix (ECM) proteins, which are less organized. The mechanical properties of the mutant organoids demonstrated increased stiffness and steady-state stiffness. These changes are associated with dysregulated mRNA and microRNA. Short-term treatment of the mutant organoids, but not the control ones, with the catalytic subunit of MMP2, which proteolytically cleaves ECM, reduced stiffness. The changes were associated with changes in water diffusion measured by MRI (Magnetic Resonance Imaging) and gene expression. We generated a model incorporating the differences in the mutant's and control brain organoid composition and organization that matches and explains our findings. Our study provides insights into the importance of the composition and organization of the ECM during human brain development and the role of LIS1 in brain structure.