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SMRT-RID mutation linked to Type I Pneumocyte Associated Respiratory Distress Syndrome via TR repression

ABSTRACT: We show that knock-in mutations of the nuclear corepressor SMRT in C57Bl6 mice (SMRTmRID) produces a novel respiratory distress syndrome (RDS) due to prematurity of the type I pneumocyte. Treatment with the anti-thyroid hormone drug, propylthiouracil (PTU), completely rescues the 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 appears 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 a second nuclear receptor, the TR, in type I pneumocyte differentiation and suggest a new type of therapeutic option in the treatment of glucocorticoid non-responsive RDS.

ORGANISM(S): Mus musculus

PROVIDER: GSE30661 | GEO | 2011/10/14

SECONDARY ACCESSION(S): PRJNA144589

REPOSITORIES: GEO

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SMRT-RID mutation linked to Type I Pneumocyte Associated Respiratory Distress Syndrome via TR repression

Project description:We show that knock-in mutations of the nuclear corepressor SMRT in C57Bl6 mice (SMRTmRID) produces a novel respiratory distress syndrome (RDS) due to prematurity of the type I pneumocyte. Treatment with the anti-thyroid hormone drug, propylthiouracil (PTU), completely rescues the 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 appears 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 a second nuclear receptor, the TR, in type I pneumocyte differentiation and suggest a new type of therapeutic option in the treatment of glucocorticoid non-responsive RDS. Total RNA was obtained from WT and SMRT-RID E18.5 lungs of embryos from mothers treated with Diet containing 0.15% PTU or control chow for 2 days (from E16.5).

2011-10-13 | E-GEOD-30661 | biostudies-arrayexpress

Expression data from mouse liver over-expressing either GFP alone or biotinylated-TRb1 and GFP

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Expression data from mouse liver over-expressing either GFP alone or biotinylated-TRb1 and GFP

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Project description:We investigated if a serum microRNA signatured correlated with the presence of thyroid-mediated developmental neurotoxicity in the rat. We isolated serum from control (euthyroid) and exposed (hypothyroid) rat pups on PN8. The maternal exposure utilized to induce developmental hypothyroidism was propylthiouracil (PTU). PTU was administered in the drinking water during pregnancy and lactation.

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NCoR1 and SMRT play unique roles in thyroid hormone signaling in the liver

Project description:NCoR1 (Nuclear receptor Co-Repressor) and SMRT (Silencing Mediator of Retinoid and Thyroid hormone receptor) are well-recognized coregulators of nuclear receptor (NR) action. However, their unique roles in the regulation of thyroid hormone (TH) signaling in specific cell types have not been determined. To accomplish this we generated a mouse model that lacked function of either NCoR1 or SMRT or both in the liver only. Despite both corepressors being present in the liver, SMRT had no ability to regulate TH signaling when deleted in either euthyroid or hypothyroid animals. In contrast, disruption of NCoR1 action confirmed that it is the principal mediator of TH sensitivity in vivo. While SMRT played little role in TH signaling alone, when disrupted in combination with NCoR1 it greatly accentuated the activation of hepatic lipogenesis regulated by NCoR1. Thus, corepressor specificity exists in vivo and NCoR1 is the principal regulator of TH action in the liver. However, both NCoR1 and SMRT collaborate to control hepatic lipogenesis and lipid storage, which likely reflects their cooperative activity in regulating the action of multiple NRs including the thyroid hormone receptor (TR). RNA was extracted from livers from 3 individual mice for each group (Double-floxed, Liver specific-SMRT knock out, and Liver specific-double knock out); all were euthyroid, female mice

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Gene expression profiling in NCoR deficient mouse livers

Project description:The thyroid hormone receptor (TR) has been proposed to regulate target genes in the absence of triiodothyronine (T3), through the recruitment of the corepressors, NCoR and SMRT. NCoR and SMRT may thus play a key role in both hypothyroidism and resistance to thyroid hormone, though this has never been tested in vivo. To accomplish this we developed mice that express in the liver a NCoR protein (L-NCoR∆ID) that cannot interact with the TR. L-NCoR∆ID mice develop normally, however when made hypothyroid the repression of many positively regulated T3-target genes is abrogated, demonstrating that NCoR plays a specific and sufficient role in repression by the unliganded TR. Remarkably, in the euthyroid state, expression of many T3-targets are also upregulated in L-NCoR∆ID mice, demonstrating that NCoR also determines the magnitude of the response to T3 in euthyroid animals. While positive T3 targets were upregulated in L-NCoR∆ID mice in the hypo and euthyroid state there was less effect seen on negatively regulated T3 target genes. Thus, NCoR is a specific regulator of T3-action in vivo and mediates the activity of the unliganded TR. Furthermore, NCoR may play a key role in determining the differences in individual responses to similar levels of circulating T3. Keywords: NCoR, thyroid hormone signaling, mouse liver, DNA Microarray To better assess the role of NCoR in positive and negative regulation we performed micorarray analysis of gene expression in the livers of euthyroid and hypothyroid control and L-NCoR∆ID mice.

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Mus musculus

Project description:SMRT-RID mutation linked to Type I Pneumocyte Associated Respiratory Distress Syndrome via TR repression

| PRJNA144589 | ENA