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

Federica Marelli, Silvia Carra, Maura Agostini, Franco Cotelli, Robin Peeters, Krishna Chatterjee, Luca Persani

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)102-117
Number of pages16
JournalMolecular and Cellular Endocrinology
Volume424
DOIs
Publication statusPublished - Mar 15 2016

Keywords

  • Resistance to thyroid hormone
  • THRA
  • THRB
  • Thyroid hormone action
  • Thyroid hormone receptors
  • Zebrafish

ASJC Scopus subject areas

  • Endocrinology
  • Molecular Biology
  • Biochemistry

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