title: Patterns of thyroid hormone receptor expression in zebrafish and generation of a novel model of resistance to thyroid hormone action.
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.
authors.affiliation: Laboratorio Sperimentale di Ricerche Endocrino-Metaboliche, Istituto Auxologico Italiano, 20149 Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Marelli
authors.affiliation: Dipartimento di Bioscienze, Università degli Studi di Milano, 20133 Milano, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Carra
authors.affiliation: Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
authors.forename: Maura
authors.initials: M
authors.lastname: Agostini
authors.affiliation: Dipartimento di Bioscienze, Università degli Studi di Milano, 20133 Milano, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Cotelli
authors.affiliation: Erasmus University, Rotterdam, NL, Netherlands.
authors.forename: Robin
authors.initials: R
authors.lastname: Peeters
authors.affiliation: Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
authors.forename: Krishna
authors.initials: K
authors.lastname: Chatterjee
authors.affiliation: Laboratorio Sperimentale di Ricerche Endocrino-Metaboliche, Istituto Auxologico Italiano, 20149 Milan, Italy; Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano, 20122 Milan, Italy. Electronic address: luca.persani@unimi.it.
authors.forename: Luca
authors.initials: L
authors.lastname: Persani
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004625:Embryo, Nonmammalian; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D009154:Mutation; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics* / Q000378:metabolism; D037042:Thyroid Hormone Receptors beta / Q000235:genetics* / Q000378:metabolism; D018382:Thyroid Hormone Resistance Syndrome / Q000235:genetics*; D013963:Thyroid Hormones / Q000378:metabolism*; D014018:Tissue Distribution; D015027:Zebrafish / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; D013963:Thyroid Hormones; D029961:Zebrafish Proteins
keywords: Resistance to thyroid hormone; THRA; THRB; Thyroid hormone action; Thyroid hormone receptors; Zebrafish