ABSTRACT
Balanced progenitor activities are crucial for the development and maintenance of high turn-over organs such as the esophagus. However, the molecular mechanisms regulating these progenitor activities in the esophagus remain to be elucidated. Here, we demonstrated that Yap is required for the proliferation of esophageal progenitor cells (EPCs) in the developing murine esophagus. We found that Yap deficiency reduces EPC proliferation and stratification whereas persistent Yap activation increases cell proliferation and causes aberrant stratification of the developing esophagus. We further demonstrated that the role of YAP signaling is conserved in the developing human esophagus by utilizing 3D human pluripotent stem cell (hPSC)-derived esophageal organoid culture. Taken together, our studies combining loss/gain-of-function murine models and hPSC differentiation support a key role for YAP in the self-renewal of EPCs and stratification of the esophageal epithelium.
Footnotes
Competing interests
The authors declare no competing or financial interests.
Author contributions
Conceptualization: D.D.B., Y.Z., B.J.v.S., A.K.R., S.S.A., W.V.C., J.Q.; Methodology: D.D.B., Y.Z., B.J.v.S., M.J., J.Q.; Validation: J.Q.; Formal analysis: D.D.B., B.J.v.S., S.S.; Investigation: D.D.B., Y.Z., B.J.v.S., M.J., S.S., H.N., J.Q.; Resources: H.N.; Writing - original draft: Y.Z., J.Q.; Writing - review & editing: D.D.B., Y.Z., A.K.R., W.V.C., J.Q.; Supervision: J.Q.; Project administration: J.Q.; Funding acquisition: J.Q.
Funding
This work in the Que lab was supported by the National Institutes of Health (DK113144, DK100342 and DK120650 to J.Q.), and the Price Family Foundation. D.D.B. was supported by the National Institutes of Health (T32-DK083256 and HL132996-02S1; Administrative Supplement, J.Q.), a training grant from the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR) (U54AI117804), the NASPGHAN Foundation/NASPGHAN George Ferry Young Investigator Award (CEGIR is part of the Rare Diseases Clinical Research Network, an initiative of the Office of Rare Diseases Research, NCATS, and is funded through collaboration between NIAID, NIDDK, and NCATS and patient advocacy groups including APFED, CURED, and EFC), and gifts from the Phyllis and Ivan Seidenberg Family Fund for Children's Digestive Health. Deposited in PMC for release after 12 months.
Supplementary information
Supplementary information available online at http://dev.biologists.org/lookup/doi/10.1242/dev.178855.supplemental
- Received April 1, 2019.
- Accepted November 11, 2019.
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