Tissue Architecture Is Required for Chromosome Segregation Fidelity in Epithelia

Abstract

Chromosome segregation is classically viewed as a cell-intrinsic process. We tested this assumption by comparing chromosome segregation fidelity in various epithelial cells in their native tissue and as dissociated cells in culture and discovered that chromosome segregation fidelity is dependent on the tissue environment. Using organoid culture systems, we show that it is tissue architecture, the cell adhesion and cell polarity patterns that define a tissue, which is responsible for the heightened chromosome segregation fidelity in tissues and that disruption of tissue architecture leads to chromosome instability. Tissue architecture enhances the cell’s ability to correct erroneous microtubule-kinetochore attachments and this enhancement is especially important for maintaining chromosome stability in the liver, a polyploid tissue with high levels of erroneous attachments. Moreover, we find that neural progenitor cells, which proliferate in a region of the brain that lacks defined architecture, maintain their polarity and chromosome segregation fidelity even when removed from their tissue environment. We show that disruption of cell polarity in epithelia recapitulates the chromosome segregation defects observed in dissociated cells, arguing that cell polarity is the critical component of tissue architecture that facilitates chromosome segregation. Our data bring us to the surprising conclusion that the external environment influences chromosome segregation across many epithelial cell types. The function of epithelial tissues requires that cells maintain distinct adhesions and polarity in both interphase and mitosis. In relinquishing autonomy over their polarity, epithelial cells also rely on their native tissue for chromosome segregation fidelity. We propose that disruption of tissue architecture could explain the chromosome instability that characterizes and drives cancer. More broadly, our observations highlight the importance of context for even the most fundamental cellular processes and thus the need to use experimental systems that maximize physiologic relevance across all areas of cell biology.