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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. 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).

ORGANISM(S): Mus musculus

SUBMITTER: Ruth Yu

PROVIDER: E-GEOD-30661 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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.

2011-10-14 | GSE30661 | GEO

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

2014-11-21 | E-GEOD-54192 | biostudies-arrayexpress

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.

2008-12-03 | E-GEOD-10001 | biostudies-arrayexpress

Gene expression profiling in NCoR deficient mouse livers

2008-12-04 | GSE10001 | GEO

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

2014-11-21 | GSE54192 | GEO

Transcriptional profile of zebrafish eyes after exposure to 350 mg/L Propylthiouracyl (PTU)

Project description:Vertebrate eye devlopment is partially regulated by thyroid hormones. Propylthiouracyl is a pharmaceutical that lowers thyroid hormone levels. We investigated the effects of PTU on eye development of zebrafish. We expected PTU exposure to cause transcriptional changes of visual-system-related genes, which find their phenotypic anchoring in eye malformations and dysfunction, as observed in our previous studies. Additionally, the reversibility of effects after recovery in clean water for three days was investigated.

2019-05-09 | GSE121334 | GEO

Mus musculus

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

| PRJNA144589 | ENA

Transcription profiling of mouse 3T3-MEFs derived from wild-type and SMRT RID mutants

Project description:SMRT (silencing mediator of retinoid and thyroid hormone receptors) is recruited by numerous transcription factors to mediate lineage and signal dependent transcriptional repression. We generated a knock-in mutation in the receptor interaction domain (RID) of SMRT (SMRTmRID) that solely disrupts its interaction with nuclear hormone receptors. SMRTmRID-derived 3T3-MEFs display a dramatically increased adipogenic capacity and accelerated differentiation rate. We measured global gene expression in wild-type versus SMRTmRID-derived 3T3-MEFs in the undifferentiated state to examine which pathways were altered. Our results demonstrate that SMRT-RID dependent repression is a key determinant of the adipogenic set point. Experiment Overall Design: 3T3 cells derived from wild-type and SMRT RID MEFs were cultured under pre-differentiated conditions prior to harvesting for RNA.

2009-01-18 | E-GEOD-13143 | biostudies-arrayexpress

Expression data from 3T3-MEFs derived from wild-type and SMRT RID mutant mice

Project description:SMRT (silencing mediator of retinoid and thyroid hormone receptors) is recruited by numerous transcription factors to mediate lineage and signal dependent transcriptional repression. We generated a knock-in mutation in the receptor interaction domain (RID) of SMRT (SMRTmRID) that solely disrupts its interaction with nuclear hormone receptors. SMRTmRID-derived 3T3-MEFs display a dramatically increased adipogenic capacity and accelerated differentiation rate. We measured global gene expression in wild-type versus SMRTmRID-derived 3T3-MEFs in the undifferentiated state to examine which pathways were altered. Our results demonstrate that SMRT-RID dependent repression is a key determinant of the adipogenic set point. Keywords: SMRTmRID expression compared to wild-type

2009-01-07 | GSE13143 | GEO

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

Project description:We over-expressed biotinylated-thyroid hormone receptor beta 1 (TRb1) in mouse liver using an adenovirus in order to perform ChIP-seq experiments. These microarrays were performed to determine gene expression changes in response to tri-iodothyronine (thyroid hormone; T3) stimulation. A control GFP adenovirus was used and gene expression from these livers was also done as a comparison. We performed microarrays from Ad-GFP-infected propylthiouracil (PTU)-fed livers injected with either saline or T3 and Ad-TRb1-GFP infected livers injected with either saline or T3. RNA was extracted from livers of biotin ligase (BirA)-expressing mice that had been infected with either Ad-GFP or Ad-TRb1, fed with PTU for 3 weeks followed by saline or T3 injections for 4 consecutive days.

2013-12-18 | E-GEOD-52433 | biostudies-arrayexpress

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