A Yap-dependent transcriptional program directs cell migration for embryo axis assembly

Abstract

The condensation of the embryo primary axis is a fundamental landmark in the establishment of the vertebrate body plan. Although the complex morphogenetic movements directing cell convergence towards the midline have been described extensively, little is known on how gastrulating cells interpret mechanical cues. Yap proteins are among the best characterized transcriptional mechanotransducers, yet their role in gastrulation has remained elusive. Here we show that the double knockout of yap and its paralog yap1b in medaka results in an axis assembly failure. Quantitative live imaging reveals that mutant cells display reduced displacement and migratory persistence. By characterizing the Yap-dependent transcriptional program, we identified genes involved in cytoskeletal organization and cell-ECM adhesion, rather than in germ layer specification, as direct Yap targets. Dynamic analysis of Tead sensors and downstream targets reveals Yap is acting in migratory cells, and not as a midline beacon, to direct gastrulating precursors trajectories by promoting cortical actin recruitment and focal adhesions assembly. We propose that Yap is engaged in a mechano-regulatory loop that is essential to maintain the directed cell migration sustaining embryo axis formation.

The Plasma Membrane and Mechanoregulation in Cells

“…YAP proteins, renowned transcriptional regulators, exhibit nuclear translocation in response to mechanical stimulation, displaying activity in the spreading of cells. 23,24 This mechanosensing capability relies on actomyosin contractility, actin capping, severing proteins, and coupling between the ECM and the nuclear envelope. 25,26 The nuclear translocation of factors like activator YAP (Figure 2a) and coactivator TAZ is switched on by suppression of the Hippo pathway via upstream mechanosignaling proteins like Ras-related GTPase RAP2 and misshapen/MAP kinase kinase kinase kinases (Msn/MAP4Ks) or Piezo1 due to an increase of ECM stiffness, stretching of cell geometry, and alterations in cytoskeletal tension.…”