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

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).

本研究证实，在C57BL/6小鼠中引入核辅阻遏蛋白SMRT的敲入突变（SMRTmRID），可因I型肺细胞成熟过早而诱发新型呼吸窘迫综合征（RDS）。使用抗甲状腺激素药物丙硫氧嘧啶（PTU）进行干预，可完全挽救SMRT诱导的RDS表型，这提示甲状腺激素受体（TR）在肺脏发育中存在此前未被发现的关键作用。本研究进一步证实，TR与SMRT可通过Klf2调控I型肺细胞的分化，而Klf2似乎可直接激活I型肺细胞的基因表达程序。与之相反，肺组织缺失Klf2的小鼠无法形成成熟的I型肺细胞，并于出生后短期内死亡，其表型与SMRTmRID小鼠高度吻合。上述研究结果明确了TR作为第二种参与I型肺细胞分化的核受体，并为糖皮质激素抵抗型RDS的治疗提供了新型干预策略。本研究从经含0.15% PTU的饲料或对照饲料干预（自E16.5起干预2天）的孕鼠胚胎中，获取了野生型（WT）与SMRT-RID E18.5胎鼠的肺组织总RNA。