A Yap-dependent mechano-regulatory loop directs cell migration for embryo axis assembly

Abstract

Gastrulation is a decisive process that occurs during embryonic development, in which a relatively homogenous group of cells is transformed into an embryo with established body axes and presenting the three germ layers. This is achieved through complex cell rearrangements that are tightly controlled by the interplay of the different types of morphogenetic inputs. In the animal kingdom, striking divergences exist in embryonic development, as they evolve and adapt to different environments, egg architecture and speed of development. However, even though large differences can be found among the different species, the underlying logic and principles governing the gastrulation movements are conserved. The set of cell movements observed during gastrulation is not exclusive to this process, as they are also generally involved in organogenesis, tissue regeneration, and cancer progression. Therefore, understanding how the gastrulation movements are coordinated and controlled is essential not only to understand axis formation, but also how tissues and organs are build, and even which are the mechanism underlying oncogenic growth and metastasis. The key role of mechanical inputs during tissue morphogenesis is becoming increasingly evident, however little is known about how these inputs shape and regulate gastrulation. Among the most well-known transcriptional activators that cells use to interpret mechanical signals are YAP proteins, yet their role in gastrulation remains elusive. Our detailed analysis of yap1 and yap1b double mutants in medaka fish shows that these mechanosensors are required for the assembly of the primary embryo axis: a key event for the establishment of the vertebrate body plan. Using quantitative imaging and live-sensors, we show that Yap activity is required for the proper migration of dorsally converging cells towards the embryo midline. Thus, mutant cells display reduced velocity and migratory persistence resulting in shorter cell displacements in many cases insufficient to reach the midline. Combining RNA-seq with previous DamID-seq data, we characterize the transcriptional program directly activated by Yap proteins, which mostly entails the recruitment of actin cytoskeleton regulators, ECM molecules and focal adhesion components. Moreover, we show that Yap activation depends itself on intracellular tension, closing a positive feedback loop that maintains directed cell migration.