A critical role for miR-142 in alveolar epithelial lineage formation in mouse lung development
The respiratory epithelium arises from alveolar epithelial progenitors which differentiate into alveolar epithelial type 1 (AT1) and type 2 (AT2) cells. AT2 cells are stem cells in the lung critical for the repair process after injury. Mechanisms regulating AT1 and AT2 cell maturation are poorly defined. We report that the activation of the glucocorticoid pathway in an in vitro alveolar epithelial lineage differentiation assay led to increased AT2 marker Sftpc and decreased miR-142 expression. Using miR-142 KO mice, we demonstrate an increase in the AT2/AT1 cell number ratio. Overexpression of miR-142 in alveolar progenitor cells in vivo led to the opposite effect. Examination of the KO lungs at E18.5 revealed enhanced expression of miR-142 targets Apc, Ep300 and Kras associated with increased β-catenin and p-Erk signaling. Silencing of miR-142 expression in lung explants grown in vitro triggers enhanced Sftpc expression as well as increased AT2/AT1 cell number ratio. Pharmacological inhibition of Ep300-β-catenin but not Erk in vitro prevented the increase in Sftpc expression triggered by loss of miR-142. These results suggest that the glucocorticoid-miR-142-Ep300-β-catenin signaling axis controls pneumocyte maturation.
KeywordsAlveolar epithelium microRNA-142 Lung EP300 Beta-catenin
We acknowledge the precious help provided by Kerstin Goth and Jana Rostkovius in managing the mouse colonies, and Shirisha Bagari for the genotyping of the mice. C.M.C. and E.E.A. were funded by start-up grants from the Cardio Pulmonary Institute (CPI) (previously known as Excellence Cluster Cardio-Pulmonary System (ECCPS)). C.M.C. also acknowledges the support of the University Hospital Giessen and Marburg (UKGM). E.E.A. acknowledges the support of the University Hospital Giessen and Marburg (UKGM) and the German Center for Lung Research (DZL). S.B. was supported by grants from the Deutsche Forschungsgemeinschaft (DFG; BE4443/1-1, BE4443/4-1, BE4443/6-1, BE4443/14-1, KFO309 P7 and SFB1213-projects A02 and A04), UKGM, Universities of Giessen and Marburg Lung Center (UGMLC) and the Deutsche Zentrum fur Lungenforschung (DZL). J.S.Z was funded through a start-up package from Wenzhou Medical University and the National Natural Science Foundation of China (Grant Number 81472601). S.H. was supported by University Hospital Giessen and Marburg (FOKOOPV), the German Center for Lung Research (DZL), and Grants from the DFG (KFO309 P2/8; SFB1021 C05, SFB TR84 B2). CC was supported by the Interventional Pulmonary Key Laboratory of Zhejiang Province, the Interventional Pulmonology Key Laboratory of Wenzhou City, the Interventional Pulmonology Innovation Subject of Zhejiang Province, the National Nature Science Foundation of China (81570075, 81770074), Zhejiang Provincial Natural Science Foundation (LZ15H010001), Zhejiang Provincial Science Technology Department Foundation (2015103253) as well as the National Key Research and Development Program of China (2016YFC1304000). B.M. acknowledges the ANR-18-CE92-0009-01.
- 2.El Agha E, Bellusci S (2014) Walking along the fibroblast growth factor 10 route: a key pathway to understand the control and regulation of epithelial and mesenchymal cell-lineage formation during lung development and repair after injury. Scientifica 2014:538379Google Scholar
- 9.Carraro G, Shrestha A, Rostkovius J, Contreras A, Chao CM, El Agha E, Mackenzie B, Dilai S, Guidolin D, Taketo MM, Gunther A, Kumar ME, Seeger W, De Langhe S, Barreto G, Bellusci S (2014) miR-142-3p balances proliferation and differentiation of mesenchymal cells during lung development. Development 141:1272–1281CrossRefGoogle Scholar
- 16.Chao CM, Yahya F, Moiseenko A, Tiozzo C, Shrestha A, Ahmadvand N, El Agha E, Quantius J, Dilai S, Kheirollahi V, Jones M, Wilhem J, Carraro G, Ehrhardt H, Zimmer KP, Barreto G, Ahlbrecht K, Morty RE, Herold S, Abellar RG, Seeger W, Schermuly R, Zhang JS, Minoo P, Bellusci S (2017) Fgf10 deficiency is causative for lethality in a mouse model of bronchopulmonary dysplasia. J Pathol 241:91–103CrossRefGoogle Scholar
- 17.Ramasamy SK, Mailleux AA, Gupte VV, Mata F, Sala FG, Veltmaat JM, Del Moral PM, De Langhe S, Parsa S, Kelly LK, Kelly R, Shia W, Keshet E, Minoo P, Warburton D, Bellusci S (2007) Fgf10 dosage is critical for the amplification of epithelial cell progenitors and for the formation of multiple mesenchymal lineages during lung development. Dev Biol 307:237–247CrossRefGoogle Scholar
- 24.Carraro G, El-Hashash A, Guidolin D, Tiozzo C, Turcatel G, Young BM, De Langhe SP, Bellusci S, Shi W, Parnigotto PP, Warburton D (2009) miR-17 family of microRNAs controls FGF10-mediated embryonic lung epithelial branching morphogenesis through MAPK14 and STAT3 regulation of E-Cadherin distribution. Dev Biol 333:238–250CrossRefGoogle Scholar