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 the type I pneumocyte, the cell that mediates gas exchange, is poorly understood. In contrast, glucocorticoids and their cognate receptor (GR) 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 corepressor SMRT in C57Bl6 mice (SMRTmRID) produces a novel respiratory distress syndrome due to prematurity of the type I pneumocyte. Though unresponsive to glucocorticoids, treatment with anti-thyroid hormone drugs (propylthiouracil or methimazole) 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.

Role of co-regulators in metabolic and transcriptional actions of thyroid hormone

“…Remarkably, the rise of TSH during hypothyroidism was also blunted in these animals, in contrast with Src1 knockout mice. While serum T 4 concentrations were slightly reduced in Smrt mRID mice on C57/BL6 background (Pei et al 2011), postnatal global ablation of SMRT had no effect on circulating T 4 levels or TSH subunit expression in the pituitary, confirming that similarly to the liver, specificity of co-repressor recruitment exists in HPT axis, and NCoR is the preferred TR co-repressor (Shimizu et al 2015). A somewhat different phenotype related to dysregulation of HPT axis was found in N-DADm mice (You et al 2010).…”

“…Interestingly, on a pure C57BL/6 background, close to 99% of Smrt mRID pups die due to a defect in the development of type 1 pneumocytes that leads to previously unknown respiratory distress syndrome (Pei et al 2011). The Smrt mRID pups could be rescued by treating the pregnant dams with antithyroid drugs propylthiouracil or methimazole, which led to a complete restoration of expression of type 1 pneumocyte markers and normal survival.…”

“…It has been proposed that co-activators and co-repressors paradoxically play the opposite roles on negative targets. The only definitive in vivo proof of co-repressors playing a role in direct transcriptional activation in the absence of TH is activation of expression of Klf2 in the lung during neonatal period (Pei et al 2011). Most studies so far found little to no role for co-regulators in the negative regulation by TH in peripheral tissues.…”

On the pulmonary toxicity of oxygen. 4. The thyroid arena

“…A new and unique perspective on this is that of Pei, et al (2011). Knock-in mutations of the nuclear co-repressor SMRT (silencing mediator of retinoid and thyroid hormone receptors) in C57BL/6 mice produced a previously identified respiratory distress syndrome caused by prematurity of type I pneumocytes, the principal peripheral lung epithelium most responsible for oxygen, carbon dioxide, and water exchange between the peripheral air spaces and the intrinsic tissue of the lung.…”

Thyroid hormone regulates muscle function during cold acclimation in zebrafish (Danio rerio)

“…Kruppel-like factor 15 (KLF-15), a transcription factor important in muscle metabolism, has recently been shown to regulate muscle performance during exercise in mice (Haldar et al, 2012). Some members of the Kruppel-like family of transcription factors are also responsive to TH (Pei et al, 2011), thus we were also interested in whether TH regulates KLF-15 muscle mRNA levels in response to cold exposure. We used a multifactorial experimental design in which we induced hypothyroidism, followed by supplementation with T 2 and T 3 (+ controls) in zebrafish exposed to different chronic and acute temperature combinations.…”