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A Gata6-Wnt pathway required for epithelial stem cell development and airway regeneration

Abstract

Epithelial organs, including the lung, are known to possess regenerative abilities through activation of endogenous stem cell populations, but the molecular pathways regulating stem cell expansion and regeneration are not well understood. Here we show that Gata6 regulates the temporal appearance and number of bronchioalveolar stem cells (BASCs) in the lung, its absence in Gata6-null lung epithelium leading to the precocious appearance of BASCs and concurrent loss in epithelial differentiation. This expansion of BASCs was the result of a pronounced increase in canonical Wnt signaling in lung epithelium upon loss of Gata6. Expression of the noncanonical Wnt receptor Fzd2 was downregulated in Gata6 mutants and increased Fzd2 or decreased β-catenin expression rescued, in part, the lung epithelial defects in Gata6 mutants. During lung epithelial regeneration, canonical Wnt signaling was activated in the niche containing BASCs and forced activation of Wnt signaling led to a large increase in BASC numbers. Moreover, Gata6 was required for proper lung epithelial regeneration, and postnatal loss of Gata6 led to increased BASC expansion and decreased differentiation. Together, these data demonstrate that Gata6-regulated Wnt signaling controls the balance between progenitor expansion and epithelial differentiation required for both lung development and regeneration.

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Figure 1: Loss of Gata6 leads to lung epithelial differentiation defects.
Figure 2: Loss of Gata6 in lung epithelium results in the precocious appearance of BASCs.
Figure 3: Increased proliferation in bronchiolar epithelium of Gata6flox/flox:Sftpc-cre mutants.
Figure 4: Fzd2 is a target of Gata6 in lung epithelium and negatively regulates canonical Wnt signaling.
Figure 5: Increased canonical Wnt signaling in lung epithelium upon loss of Gata6 expression and rescue of these defects by reexpression of Fzd2 or decreased β-catenin expression.
Figure 6: Canonical Wnt signaling is activated upon lung regeneration and forced activation of Wnt–β-catenin signaling leads to expansion of BASCs.
Figure 7: Gata6 regulates BASC expansion and differentiation in airway epithelial regeneration.

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Acknowledgements

The authors thank J. Epstein and C. Simon for helpful suggestions and critical reading of the manuscript. We thank S. Piccolo (University of Padua) for providing the BAT-lacZ mice, M. Taketo (Kyoto University) for providing the Ctnnb1ex3flox mice and M.M. Lu for excellent technical assistance with the histological studies. These studies were supported by funding from the US National Institutes of Health to E.E.M. (HL064632, HL075215, and HL087825) and to M.S.P. (HL075215).

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Y.Z. and E.E.M. developed the project; Y.Z., A.M.G., E.D.C., J.J.L. and R.K. performed mouse genetics experiments; K.M. and Y.Z. performed cell culture experiments; J.Y. performed histology experiments; F.J.D., J.A.W. and M.S.P. contributed materials; and Y.Z. and E.E.M. wrote the paper.

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Correspondence to Edward E Morrisey.

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Zhang, Y., Goss, A., Cohen, E. et al. A Gata6-Wnt pathway required for epithelial stem cell development and airway regeneration. Nat Genet 40, 862–870 (2008). https://doi.org/10.1038/ng.157

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