Thyroid Hormone Nuclear Receptors in Health and Disease

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Elucidated that TRalpha1 mutants suppress KLF9 signaling to impair female fertility. Since the creation of Thra1PV/+ mice, we have observed impaired fertility in female mutant mice. This mutant mouse provided an opportunity to understand how thyroid dysfunctions could lead to abnormal female reproduction in humans. The Thra1PV/+ mutant mouse exhibited atrophied uterus, loss of glands, squamous metaplasia, and fibrosis in the endometrium. RNA-seq analysis of laser-captured micro-dissected endometrium and spatial transcriptomics revealed a key role for Krüppel-like factor (Klf9), a directly regulated TRalpha1 target gene, in normal endometrial differentiation. Klf9 was suppressed in mutant endometrium, and pathway analysis revealed that deficient Klf9 signaling was associated with keratinocyte differentiation, consistent with the endometrial metaplasia observed histologically. These metaplastic cells were the source of ectopic IL33, which led to T-cell infiltrates, destruction of glands, and endometrial fibrosis, culminating in infertility. This study uncovers a link between TRalpha1 and KLF9 signaling for normal endometrial differentiation, reveals a mechanism for ectopic uterine IL33 in female infertility. As far as we know, our study is the first to clearly demonstrate that TRalpha1directly impacts female reproduction in humans. Discovered that TRalpha1 mutants impair female fertility in zebrafish models of RTHalpha. Hypothyroidism is well known to impact female reproduction. However, TR's role in female reproduction biology is somewhat limited, especially during development. The zebrafish model of RTHalpha, in which the thrab gene is mutated, resulted in female infertility. Though homozygous female mutants (thrabm/m) showed normal ovarian development and folliculogenesis before sexual maturation, they failed to release eggs during oviposition after sexual maturation. This spawning failure was due to oviductal blockage at the genital papilla. The obstruction of the oviduct subsequently caused an accumulation of the eggs in the ovary, resulting in severe ovarian hypertrophy, abdominal distention, and disruption of folliculogenesis. We have previously demonstrated that the functions of TRalpha1 mutant are highly conserved among humans, mice and zebrafish. These findings provide compelling evidence to show that TRalpha1 plays a critical role in female fertility and reproductive health in early development.