title: Thyroid hormone receptor repression is linked to type I pneumocyte-associated respiratory distress syndrome.
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.
authors: Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, California, USA.
authors: Liming
authors: L
authors: Pei
authors: Mathias
authors: M
authors: Leblanc
authors: Grant
authors: G
authors: Barish
authors: Annette
authors: A
authors: Atkins
authors: Russell
authors: R
authors: Nofsinger
authors: Jamie
authors: J
authors: Whyte
authors: David
authors: D
authors: Gold
authors: Mingxiao
authors: M
authors: He
authors: Kazuko
authors: K
authors: Kawamura
authors: Hai-Ri
authors: HR
authors: Li
authors: Michael
authors: M
authors: Downes
authors: Ruth T
authors: RT
authors: Yu
authors: Henry C
authors: HC
authors: Powell
authors: Jerry B
authors: JB
authors: Lingrel
authors: Ronald M
authors: RM
authors: Evans
mesh_terms: D056809:Alveolar Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D020869:Gene Expression Profiling; D055879:Gene Knock-In Techniques; D006801:Humans; D007231:Infant, Newborn; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046228:Microarray Analysis; D056985:Nuclear Receptor Co-Repressor 2 / Q000235:genetics / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism; D012127:Respiratory Distress Syndrome, Newborn / Q000378:metabolism*
chemical_list: C498314:Klf2 protein, mouse; D051741:Kruppel-Like Transcription Factors; C539131:Ncor2 protein, mouse; D056985:Nuclear Receptor Co-Repressor 2; D011965:Receptors, Glucocorticoid; D011988:Receptors, Thyroid Hormone