Endocrine Abstracts

Thyroid hormone action defects (THADs) are caused by the defective action of thyroid hormones (THs) through their receptors (TRs). TRs variants (TRα1 or TRβ) are associated with several defects, which depend mainly on the tissue-specific expression of the defective-receptor. One of the most striking manifestations is the deregulation of the hypothalamus–pituitary–thyroid axis (HPT); patients with TRα1-mutations show normal thyroid volume, low T4/T3 and high T3/rT3 ratios. Conversely, patients carrying TRβ-mutations exhibit goitre, high T4 and T3 production with unsuppressed TSH. In this study we take advantage of the zebrafish model to further understand the role TRs during development and in the HPT axis regulation. The tissue-specific expression of TRs are analysed by RQ-PCR and whole mount in situ hybridization at several developmental-stages. We than create two different mutant-lines (MOs_TRα1 and MOs_TRβ) using specific morpholinos, and we studied the of the HPT axis by several techniques. In zebrafish the expression of TRs is temporally and tissue-specific regulated. During the embryonic development, TRs are expressed during the first 4 h-post-fertilization (hpf), followed by a down-regulation window until 24 hpf, when the expression is again up-regulated in tissue-specific manner: TRα1 is prevalently expressed in brain, heart, thyroid, and gastrointestinal tract; TRβ is prevalently expressed in the pituitary, eyes and otic vesicles. The generation of different ‘heterozygous-like’ mutant-lines by specific antisense-RNAs shows that MOs_TRα1 exhibit low thyroid volume, low TSHβ and T4 production but high T3 content. Conversely, MOs_TRβ present high thyroid volume, high T4 and T3 content but unsuppressed TSHβ. In conclusion, the TRs are expressed in a temporal and tissue-specific manner revealing novel insights on TH-dependent developmental effects. The TR-mutants recapitulate the HTP axis alterations found in patients with the two forms of THADs, representing a new useful biotool to test human TRα and TRβ variants.