Thyroid hormone receptor repression is linked to type i pneumocyte-associated respiratory distress syndrome

Liming Pei, Mathias Leblanc, Grant Barish, Annette Atkins, Russell Nofsinger, Jamie Whyte, David Gold, Mingxiao He, Kazuko Kawamura, Hai Ri Li, Michael Downes, Ruth T. Yu, Henry C. Powell, Jerry B. Lingrel, Ronald M. Evans*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

55 Scopus citations


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 languageEnglish (US)
Pages (from-to)1466-1472
Number of pages7
JournalNature Medicine
Issue number11
StatePublished - Nov 2011

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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