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Thyroid Hormone Receptor Repression Linked to Type I Pneumocyte Associated Respiratory Distress Syndrome
- Source :
- Nature medicine
- Publication Year :
- 2011
-
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.
- Subjects :
- medicine.medical_specialty
Cell type
Cellular differentiation
Kruppel-Like Transcription Factors
Biology
General Biochemistry, Genetics and Molecular Biology
Article
03 medical and health sciences
Mice
0302 clinical medicine
Receptors, Glucocorticoid
Internal medicine
medicine
Animals
Humans
Nuclear Receptor Co-Repressor 2
Type-I Pneumocytes
Gene Knock-In Techniques
Lung
Type-I Pneumocyte
Cells, Cultured
030304 developmental biology
Nuclear receptor co-repressor 2
Mice, Knockout
0303 health sciences
Respiratory Distress Syndrome, Newborn
Thyroid hormone receptor
Receptors, Thyroid Hormone
Respiratory distress
Gene Expression Profiling
Infant, Newborn
Cell Differentiation
General Medicine
Fibroblasts
Microarray Analysis
3. Good health
Mice, Inbred C57BL
Endocrinology
medicine.anatomical_structure
Alveolar Epithelial Cells
Female
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 1546170X and 10788956
- Volume :
- 17
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- Nature medicine
- Accession number :
- edsair.doi.dedup.....5127c117faf0d0f7d822a08ad7d99949