YAP establishes epiblast responsiveness to inductive signals for germ cell fate.

Saya Kagiwada,Kenjiro Adachi,Borami Shin,Guangming Wu,Eva Kutejova,Karin Hübner,David Obridge,Jeffrey L Wrana,Shinya Aramaki,Hans R Schöler

doi:10.1242/dev.199732

Abstract

ABSTRACTThe germ cell lineage in mammals is induced by the stimulation of pluripotent epiblast cells by signaling molecules. Previous studies have suggested that the germ cell differentiation competence or responsiveness of epiblast cells to signaling molecules is established and maintained in epiblast cells of a specific differentiation state. However, the molecular mechanism underlying this process has not been well defined. Here, using the differentiation model of mouse epiblast stem cells (EpiSCs), we have shown that two defined EpiSC lines have robust germ cell differentiation competence. However, another defined EpiSC line has no competence. By evaluating the molecular basis of EpiSCs with distinct germ cell differentiation competence, we identified YAP, an intracellular mediator of the Hippo signaling pathway, as crucial for the establishment of germ cell induction. Strikingly, deletion of YAP severely affected responsiveness to inductive stimuli, leading to a defect in WNT target activation and germ cell differentiation. In conclusion, we propose that the Hippo/YAP signaling pathway creates a potential for germ cell fate induction via mesodermal WNT signaling in pluripotent epiblast cells.

Highlights

Germ cells are highly specialized cells that enable the transmission of genetic information and the development of a new complete organism, linking the successive generations of organisms
Using the differentiation model of epiblast stem cells (EpiSCs), we have shown that two defined EpiSC lines have robust germ cell differentiation competence
By evaluating the molecular basis of EpiSCs with distinct germ cell differentiation competence, we identified YAP/YAP1/YAP65, an intracellular mediator of the Hippo signaling pathway, as a critical mediator for establishing germ cell induction

Summary

Introduction

Germ cells are highly specialized cells that enable the transmission of genetic information and the development of a new complete organism, linking the successive generations of organisms. The WNT/ß-CATENIN signaling pathway has been shown to cooperatively regulate germ cell fate (Aramaki et al, 2013; Ohinata et al, 2009), in addition to its well-defined function in pan-mesoderm development (Huelsken et al, 2000; Liu et al, 1999). These previous studies suggest that germ cell fate is induced together with other somatic mesoderm lineages downstream of common mesodermal signaling at the onset of gastrulation. Recent studies have shown that mesodermal factors such as T/Brachyury are required for germ cell specification and directly regulate germ cell determinants in the specific pluripotent cell state, suggesting that there is context-dependent induction of mesodermal lineages including the germline and somatic cell lineages (Aramaki et al, 2013; Aramaki et al, 2021; Chen et al, 2017; Kojima et al, 2017)

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