Patterns of thyroid hormone receptor expression in zebrafish and generation of a novel model of resistance to thyroid hormone action

Molecular and Cellular Endocrinology
Federica MarelliLuca Persani

Abstract

Resistance to thyroid hormone can be due to heterozygous, dominant negative (DN) THRA (RTHα) or THRB (RTHβ) mutations, but the underlying mechanisms are incompletely understood. Here, we delineate the spatiotemporal expression of TH receptors (TRs) in zebrafish and generated morphants expressing equivalent amounts of wild-type and DN TRαs (thraa_MOs) and TRβs (thrb_MOs) in vivo. Both morphants show severe developmental abnormalities. The phenotype of thraa_MOs includes brain and cardiac defects, but normal thyroid volume and tshba expression. A combined modification of dio2 and dio3 expression can explain the high T3/T4 ratio seen in thraa_MOs, as in RTHα. Thrb_MOs show abnormal eyes and otoliths, with a typical RTHβ pattern of thyroid axis. The coexpression of wild-type, but not mutant, human TRs can rescue the phenotype in both morphants. High T3 doses can partially revert the dominant negative action of mutant TRs in morphant fish. Therefore, our morphants recapitulate the RTHα and RTHβ key manifestations representing new models in which the functional consequences of human TR mutations can be rapidly and faithfully evaluated.

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Citations

Jun 4, 2016·General and Comparative Endocrinology·Prakash SharmaReynaldo Patiño
Nov 5, 2016·Thyroid : Official Journal of the American Thyroid Association·Federica MarelliLuca Persani
Apr 19, 2018·Molecular Biology and Evolution·Gaurab K SarangiSergi Castellano
Dec 22, 2017·F1000Research·Federica Marelli, Luca Persani
Mar 1, 2019·The Journal of Endocrinology·Anne M HoubrechtsVeerle M Darras
Apr 3, 2019·International Journal of Molecular Sciences·Lisa BaumannLucia Vergauwen
Oct 25, 2017·PLoS Genetics·Shannon N RomanoDaniel A Gorelick
May 24, 2019·Acta Physiologica·Jean-David GothiéSylvie Remaud
Jan 19, 2020·Thyroid : Official Journal of the American Thyroid Association·Cho Rong HanSheue-Yann Cheng
Apr 26, 2020·International Journal of Molecular Sciences·Henrik HolbechLisa Baumann
Apr 2, 2019·Frontiers in Endocrinology·Iván LazcanoAurea Orozco
Dec 5, 2019·Thyroid : Official Journal of the American Thyroid Association·Giuditta RuraleLuca Persani

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