Introduction: Trisomy 21 or Down Syndrome (DS) patients have a predisposition for Congenital Hypothyroidism which can aggravate their mental status.
Hypothesis: The presence of three copy of Dyrk1a gene, localized in chromosome 21 in Humans, is responsible for a thyroidal dysgenesis.
Our aim is to understand the molecular mechanisms underlying this condition.
Methods: The transgenic Dyrk1a (TgDyrk1a) mouse, our DS murine model, contains three copies of the Dyrk1a gene and was obtained through electroporation of a Bacterial Artificial Chromosome containing the entire gene with its own regulatory sequences. We studied their thyroidal phenotype in young adults (813 weeks old) by histology, immunohistochemistry and blood T4 hormonal dosages, reflecting the thyroidal function. We compared the thyroidal molecular phenotype of the TgDyrk1a and wild type mice: RNA levels of molecules involved in the thyroidogenesis were studied by qRT-PCR at different embryonic stages.
Results: The average surface of thyroidal follicles in young adult TgDyrk1a mice is smaller (TgDyrk1a: 2164 μm2 versus wild type: 1420 μm2; P=0.005; n=6). They presented also a lower plasmatic T4 (TgDyrk1a: 2.4 ng/ml versus wild type: 3.7 ng/ml; P=0.019; n=14). The overexpression of Dyrk1a in the thyroids leads to an elevation of RNA level expression of Nkx2-1, Foxe1, Thyroperoxidase and Thyroglobulin, involved in thyroidogenesis, at E13.5 and E17.5.
Conclusion: Our first results show an abnormal thyroid function and histology in young adult TgDyrk1a mice and an overexpression of thyroidal developmental molecules. To further understand the molecular mechanism linking Dyrk1a overexpression to altered thyroid folliculogenesis and function we are studying some candidates as direct targets of Dyrk1a using thyroidal cell lines.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This work was supported. Supported by Sandoz SAS, EDF and the Fondation Lejeune. T4 dosage courtesy of Pr S Refetoff, Chicago.