Thyroid Hormone Nuclear Receptors in Health and Disease

Division Of Basic Sciences - Nci

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Abstract

Understanding of in vivo molecular actions of the TRalpha1 mutants has been limited since the initial identification of patients with THRA mutations. However, by using Thra1PV/+ mice we have elucidated how TRalpha1 mutants act to cause pathological manifestations in patients. Patients exhibit anemia and other hematopoiesis disorders. Using Thra1PV/+ mice, we discovered that TRa1 mutants impair erythropoiesis, via repression of the Gata-1 gene expression and its downstream regulated genes, causing anemia. Subsequently in 2021, using Thra1PV/+ mice, we found a significant reduction of B cells, but notT cells, in the peripheral circulation, bone marrow, and spleen of Thra1PV/+ mice. The expression of key transcription regulators of B cell development, such as Ebf1, Tcf3, and Pax5, was significantly decreased in the bone marrow and spleen of Thra1PV/+ mice. We further elucidated that the Ebf1 gene, essential for lineage specification in the early B cell development, was directly regulated by TRalpha1. Thus, mutations of TRalpha1 could impair B cell development in the bone marrow via suppression of key regulators of B lymphopoiesis. regulators, Ebf1, Tcf3, and Pax5, by TRa1 mutations. These findings suggest that the mutations of the THRA gene in patients could lead to B cell deficiency. Recently we have generated novel RTHalpha models in zebrafish to facilitate the study of the pathogenetic actions of TRalpha1 mutants in early development. We cannot use the Thra1PV/+ mouse to study TRalpha1 mutants in early development because of the insurmountable difficulty obtaining sufficient mutant embryos. Zebrafish have been increasingly used as models for human diseases owing to their high fecundity, rapid external embryonic development, and the easy visualization of transparent embryos. Using ThrabGlu394* and ThraaLeu405Glufs*6 mutant fish lines, we found both a dilated atrium and an abnormally shaped ventricle in adult mutant fish. The retention of red blood cells in the two abnormal heart chambers, and the decreased circulating blood speed and reduced expression of contractile genes indicated weakened contractility in the heart of mutant fish. These abnormalities were detected in mutant fish as early as 35 days postfertilization (juveniles). Furthermore, the expression of genes associated with the sarcomere assembly was suppressed in the heart of mutant fish, resulting in abnormalities of sarcomere organization as revealed by transmission electron microscopy, suggesting that the abnormal sarcomere organization could underlie the bradycardia exhibited in mutant fish. These findings provide new insights into the bradycardia found in RTHalpha patients. Taken all together, our findings from using RTHalpha models of Thra1PV/+ mice and ThrabGlu394* and ThraaLeu405Glufs*6 mutant fish, have advanced our understanding of TRalpha1 mutant actions in RTH patients with mutation of THRA gene.