Maternal thyroid hormones are transcriptionally active during embryo-foetal development: Results from a novel transgenic mouse model

Carmelo Nucera, Patrizia Muzzi, Cecilia Tiveron, Antonella Farsetti, Federico La Regina, Benedetta Foglio, Shou Ching Shih, Fabiola Moretti, Linda Della Pietra, Francesca Mancini, Ada Sacchi, Francesco Trimarchi, Alessandro Vercelli, Alfredo Pontecorvi

Research output: Contribution to journalArticlepeer-review

Abstract

Even though several studies highlighted the role of maternal thyroid hormones (THs) during embryo-foetal development, direct evidence of their interaction with embryonic thyroid receptors (TRs) is still lacking. We generated a transgenic mouse model ubiquitously expressing a reporter gene tracing TH action during development. We engineered a construct (TRE2×) containing two TH-responsive elements controlling the expression of the LacZ reporter gene, which encodes β-galactosidase (β-gal). The specificity of the TRE2× activation by TH was evaluated in NIH3T3 cells by cotransfecting TRE2× along with TRs, retinoic or oestrogen receptors in the presence of their specific ligands. TRE2× transgene was microinjected into the zygotes, implanted in pseudopregnant BDF1 (a first-generation (F1) hybrid from a cross of C57BL/6 female and a DBA/2 male) mice and transgenic mouse models were developed. β-gal expression was assayed in tissue sections of transgenic mouse embryos at different stages of development. In vitro, TRE2× transactivation was observed only following physiological T3 stimulation, mediated exclusively by TRs. In vivo, β-gal staining, absent until embryonic day 9.5-10.5 (E9.5-E10.5), was observed as early as E11.5-E12.5 in different primordia (i.e. central nervous system, sense organs, intestine, etc.) of the TRE2× transgenic embryos, while the foetal thyroid function (FTF) was still inactive. Immunohistochemistry for TRs essentially colocalized with β-gal staining. No β-gal staining was detected in embryos of hypothyroid transgenic mice. Importantly, treatment with T3 in hypothyroid TRE2× transgenic mice rescued β-gal expression. Our results provide in vivo direct evidence that during embryonic life and before the onset of FTF, maternal THs are transcriptionally active through the action of embryonic TRs. This model may have clinical relevance and may be employed to design end-point assays for new molecules affecting THs action.

Original languageEnglish
Pages (from-to)2417-2435
Number of pages19
JournalJournal of Cellular and Molecular Medicine
Volume14
Issue number10
DOIs
Publication statusPublished - Oct 2010

Keywords

  • Central nervous system
  • Embryonic development
  • Maternal thyroid hormone
  • Reporter gene
  • Thyroid receptors
  • Thyroid responsive element
  • Transgenic mouse

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Medicine

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