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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.

journal_name

Mol Cell Endocrinol

journal_title

Molecular and cellular endocrinology

authors

Marelli F,Carra S,Agostini M,Cotelli F,Peeters R,Chatterjee K,Persani L

doi

10.1016/j.mce.2016.01.020

subject

Has Abstract

pub_date

2016-03-15 00:00:00

pages

102-17

eissn

0303-7207

issn

1872-8057

pii

S0303-7207(16)30020-X

journal_volume

424

pub_type

杂志文章

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