Endodermal cells use contact inhibition of locomotion to achieve uniform cell dispersal during zebrafish gastrulation

The endoderm is one of the three primary germ layers that gives rise to the gastrointestinal and respiratory epithelia and other tissues. Prior to epithelium formation, endodermal cells are highly migratory with only transient interactions among each other. Here, we show that, in zebrafish embryos, early-stage migratory endodermal cells actively avoid each other through contact inhibition of locomotion (CIL) and that this response is dependent on the Rho GTPase RhoA. Computational modeling predicted that CIL is required for the efficient and uniform dispersal characteristic of endodermal cells. Consistent with our model, we found that experimentally suppressing CIL resulted in irregular clustering of cells within the endoderm. Finally, we found that type A Eph receptors are required to mediate endodermal CIL. Together, our results suggest that endodermal cells use EphA- and RhoA-dependent CIL as a cell dispersal and spacing mechanism, demonstrating how tissue-scale patterns can emerge from local cell-cell interactions.