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Thyroid hormone receptor repression is linked to type I pneumocyte–associated respiratory distress syndrome

Nature Medicine volume 17, pages 14661472 (2011) | Download Citation

Abstract

Although the lung is a defining feature of air-breathing animals, the pathway controlling the formation of type I pneumocytes, the cells that mediate gas exchange, is poorly understood. In contrast, the glucocorticoid receptor and its cognate ligand have long been known to promote type II pneumocyte maturation; prenatal administration of glucocorticoids is commonly used to attenuate the severity of infant respiratory distress syndrome (RDS). Here we show that knock-in mutations of the nuclear co-repressor SMRT (silencing mediator of retinoid and thyroid hormone receptors) in C57BL/6 mice (SMRTmRID) produces a previously unidentified respiratory distress syndrome caused by prematurity of the type I pneumocyte. Though unresponsive to glucocorticoids, treatment with anti–thyroid hormone drugs (propylthiouracil or methimazole) completely rescues SMRT-induced RDS, suggesting an unrecognized and essential role for the thyroid hormone receptor (TR) in lung development. We show that TR and SMRT control type I pneumocyte differentiation through Klf2, which, in turn, seems to directly activate the type I pneumocyte gene program. Conversely, mice without lung Klf2 lack mature type I pneumocytes and die shortly after birth, closely recapitulating the SMRTmRID phenotype. These results identify TR as a second nuclear receptor involved in lung development, specifically type I pneumocyte differentiation, and suggest a possible new type of therapeutic option in the treatment of RDS that is unresponsive to glucocorticoids.

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Acknowledgements

We thank H. Juguilon, M. Karunasiri, S. Kaufman and Y. Dayn for technical support, J. Stubbs, C. Kintner, L. Nagy, S.-H. Hong, J. Jonker and J. Fitzpatrick for helpful discussions, M. Montminy of Salk Institute for GFP adenovirus, J. Simon, L. Grabowski and J. Belcovson for artistic work, and E. Ong and S. Ganley for administrative assistance. We appreciate the help and expertise from M. Wood for the electron microscopy study. We thank J. Codey and the Leona M. and Harry B. Helmsley Charitable Trust for their generous support. L.P. is a Parker B. Francis Fellow supported by the Francis Family Foundation. R.M.E. is an investigator of the Howard Hughes Medical Institute at the Salk Institute for Biological Studies and March of Dimes Chair in Molecular and Developmental Biology. This work was supported by the Howard Hughes Medical Institute and US National Institutes of Health grants 2RO1DK057978, 2RO1HL105278, 5U19DK062434 (R.M.E.) and RO1HL57281 (J.B.L.).

Author information

Affiliations

  1. Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, California, USA.

    • Liming Pei
    • , Annette Atkins
    •  & Ronald M Evans
  2. Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA.

    • Liming Pei
    • , Mathias Leblanc
    • , Grant Barish
    • , Annette Atkins
    • , Russell Nofsinger
    • , Jamie Whyte
    • , David Gold
    • , Mingxiao He
    • , Kazuko Kawamura
    • , Michael Downes
    • , Ruth T Yu
    •  & Ronald M Evans
  3. Department of Pathology, University of California–San Diego, La Jolla, California, USA.

    • Hai-Ri Li
    •  & Henry C Powell
  4. Department of Molecular Genetics, Biochemistry and Microbiology, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA.

    • Jerry B Lingrel

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Contributions

L.P. led the project and designed and performed most of the experiments. M.L. is a pathologist who evaluated all the anatomy, histology and staining results. A.A. analyzed the blood T4 and rT3 levels in newborn pups using mass spectrometry. R.N. generated the SMRT knock-in mice. R.T.Y. analyzed the microarray data. H.-R.L. provided expertise in electron microscopy studies. G.B., J.W., D.G., M.H., K.K., M.D., H.C.P. and J.B.L. provided intellectual input and technical expertise. J.B.L. provided the Klf2−/− ES cells. R.M.E. supervised the project. L.P. and R.M.E. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Ronald M Evans.

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DOI

https://doi.org/10.1038/nm.2450

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