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

ABSTRACT: The 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.

SUBMITTER: Kagiwada S

PROVIDER: S-EPMC8571999 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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

Kagiwada Saya S Aramaki Shinya S Wu Guangming G Shin Borami B Kutejova Eva E Obridge David D Adachi Kenjiro K Wrana Jeffrey L JL Hübner Karin K Schöler Hans R HR

Development (Cambridge, England) 20211019 20

The 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), ...[more]

PMID: 34528691

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Project description:Teeth develop from reciprocal signaling between inductive and receptive cells. The inductive signals for tooth development are initially in the epithelium of the developing branchial arch, but later shift to the underlying mesenchyme of a developing tooth germ. The inductive signals that are needed for tooth development have not yet been fully identified. Our lab previously provided a basis for bioengineering new teeth by separating the tooth germ's epithelial and mesenchyme cells into a single cell population and recombing them. This approach, however, is not clinically applicable as the cells lose their inductive ability when expanded in vitro. In this study, we investigate whether the secretome and small extracellular vehicles (sEV) derived from inductive tooth germ mesenchyme can contribute to inductive signals required for tooth development. To address this, small extracellular vesicles and secretome were purified from inductive tooth germ mesenchyme and characterized. We investigated the proteome of sEV and proteome of inductive tooth germ mesenchyme and the impact of the culture condition and duration on the proteome. Additionally, we investigated the transcriptomic changes in tooth germ epithelium after treatment with sEV from inductive tooth germ mesenchyme. We show that culture duration of inductive tooth germ mesenchyme has an impact on the proteome of sEV purified from these cells. Similarly, culturing these cells in 2D and 3D environments results in different protein content. Proteome unique to sEV derived from inductive shows an association with multiple signaling pathways related to tooth development. Our RNASeq results show that treatment of tooth germ epithelial cells with small extracellular vesicles derived from inductive tooth germ mesenchyme results in an increased expression of some of the known odontogenic genes. Whilst further analysis is required to harvest the full potential of these sEV, our results suggests that extracellular vehicles contribute to signals required during tooth development, potentially through modulation of cellular metabolism and ECM organization.

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

Publications

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

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