Actin dynamics and the Bmp pathway drive apical extrusion of proepicardial cells

The epicardium, the outer mesothelial layer enclosing the myocardium, plays key roles in heart development and regeneration. During embryogenesis, the epicardium arises from the proepicardium (PE), a cell cluster that appears in the dorsal pericardium (DP) close to the venous pole of the heart. Little is known about how the PE emerges from the pericardial mesothelium. Using a zebrafish model and a combination of genetic tools, pharmacological agents and quantitative in vivo imaging, we reveal that a coordinated collective movement of DP cells drives PE formation. We found that Bmp signaling and the actomyosin cytoskeleton promote constriction of the DP, which enables PE cells to extrude apically. We provide evidence that cell extrusion, which has been described in the elimination of unfit cells from epithelia and the emergence of hematopoietic stem cells, is also a mechanism for PE cells to exit an organized mesothelium and fulfil their developmental fate to form a new tissue layer, the epicardium.N.M. was funded by the Spanish Ministry of Economy and Competitiveness through grant BFU2014–56970–P (Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016. Programa Estatal de I+D+i Orientada a los Retos de la Sociedad Retos Investigación: Proyectos I+D+i 2016, del Ministerio de Economía competitividad e Industria), and co-funding by Fondo Europeo de Desarrollo Regional (FEDER). N.M. is also supported by the Swiss National Science Foundation grant ANR-SNF 310030E-164245 and the ERC starting grant 337703. L.A-D was funded through the postdoctoral fellowship Ayudas Postdoctorales 2013-2016121212. JL de la Pompa was supported by grants SAF2016-78370-R, CB16/11/00399 (CIBER CV) and RD16/0011/0021 (TERCEL) from the Spanish Ministry of Economy, Industry and Competitiveness (MEIC). J. Vermot is supported by ANR-15-CE13-0015 – liveheart and M. Peralta by a 708312 - ZEBRA-VALVE EU project. The CNIC is supported by the Ministry of Economy, Industry and Competitiveness (MEIC) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (MEIC award SEV-2015-0505).S