SCRIB controls apical contractility during epithelial differentiation

Using an organ-on-chip model, Boeda et al. elucidate how SCRIB controls cell and tissue shape during gut epithelium differentiation. They identify a conserved binding site for SHROOM in the SCRIB carboxy-terminal domain and show that SCRIB acts as a scaffold for SHROOM2/4 and ROCK1 to control phospho-myosin polarization. Although mutations in the SCRIB gene lead to multiple morphological organ defects in vertebrates, the molecular pathway linking SCRIB to organ shape anomalies remains elusive. Here, we study the impact of SCRIB-targeted gene mutations during the formation of the gut epithelium in an organ-on-chip model. We show that SCRIB KO gut-like epithelia are flatter with reduced exposed surface area. Cell differentiation on filters further shows that SCRIB plays a critical role in the control of apical cell shape, as well as in the basoapical polarization of myosin light chain localization and activity. Finally, we show that SCRIB serves as a molecular scaffold for SHROOM2/4 and ROCK1 and identify an evolutionary conserved SHROOM binding site in the SCRIB carboxy-terminal that is required for SCRIB function in the control of apical cell shape. Our results demonstrate that SCRIB plays a key role in epithelial morphogenesis by controlling the epithelial apical contractility during cell differentiation.