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 (SMRT mRID) 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 SMRT mRID 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1466-1472 |
| Number of pages | 7 |
| Journal | Nature Medicine |
| Volume | 17 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 2011 |
Funding
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.).
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology