Markova, B. | bioRxiv Science

bioRxiv2023

The highly and perpetually upregulated thyroglobulin gene is a hallmark of functional thyrocytes

Abnormalities are indispensable for studying normal biological processes and mechanisms. In the present work, we draw attention to the remarkable phenomenon of a perpetually and robustly upregulated gene, the thyroglobulin gene (Tg). The gene is expressed in the thyroid gland and, as it has been recently demonstrated, forms so-called transcription loops, easily observable by light microscopy. Using this feature, we show that Tg is expressed at a high level from the moment a thyroid cell acquires its identity and both alleles remain highly active over the entire life of the cell, i.e. for months or years depending on the species. We demonstrate that this high upregulation is characteristic of thyroglobulin genes in all major vertebrate groups. We provide evidence that Tg is not influenced by the thyroid hormone status, does not oscillate round the clock and is expressed during both the exocrine and endocrine phases of thyrocyte activity. We conclude that the thyroglobulin gene represents a valuable model to study the maintenance of a high transcriptional upregulation. SUMMARY STATEMENTThe thyroglobulin gene is highly and permanently expressed in thyrocytes of all vertebrates, at any condition and round the clock, offering a unique model to study mechanisms of high upregulation maintenance and chromatin dynamics

cell biology↗

bioRxiv2022

Triac treatment prevents neurodevelopmental and locomotor impairments in Mct8/Oatp1c1 double knockout mice.

BackgroundPatients with inactive thyroid hormone (TH) transporter MCT8 display intellectual disability due to an insufficient TH transport and action in the CNS. As a therapeutic strategy, application of Triac (3, 5, 3-triiodothyroacetic acid) and Ditpa (3, 5 -diiodo-thyropropionic acid) have been proposed as both thyromimetic compounds are not dependent on MCT8 for cellular entry. Here, we tested and directly compared the thyromimetic actions of Triac versus Ditpa in Mct8/Oatp1c1 double knockout mice (Dko), a mouse model for human MCT8 deficiency. MethodsNewborn Dko mice were daily injected during the first three postnatal weeks with either Triac (50 ng/g or 400 ng/g) or Ditpa (400 ng/g or 4000 ng/g) and compared with Wt and Dko mice receiving saline injections. A second cohort of Dko mice was daily injected with Triac (400 ng/g) only between postnatal week 3 and 6. Thyromimetic effects in the CNS and peripheral tissues were monitored at different postnatal time points by immunofluorescence stainings for neural marker proteins, in situ hybridization and quantitative real time PCR. Locomotor performance was assessed in rotarod and hanging wire test. Acute brain slices of Triac treated Dko mice and their respective controls were used for electrophysiological recordings. ResultsOnly Dko mice injected with Triac (400 ng/g) during the first three postnatal weeks showed normalized myelination, differentiation of cortical GABAergic interneurons as well as locomotor performance. Electrophysiological recordings revealed an increased frequencies of cortical spontaneous miniature inhibitory postsynaptic currents in Dko mice and a normalization of this parameter in Triac treated Dko mice. In comparison, treatment of Dko mice with Ditpa at 4000 ng/g during the first three postnatal weeks resulted in normal myelination and cerebellar development but was less effective in restoring neuronal parameters and locomotor function. Finally, Triac was more potent than Ditpa in suppressing Trh and Tshb expression, respectively, and exerts stronger thyromimetic effects in liver and kidneys. ConclusionsIn newborn Dko deficient mice, Triac is highly effective and more efficient than Ditpa in promoting CNS maturation and function. Yet, Triac treatment needs to be initiated directly after birth to achieve the most beneficial effects.

neuroscience↗