SUN-038 - Hypothyroidism Causes Downregulation of Id2 Expression in Mouse Pituitary Stem Cells

Thyroid hormones (TH), primarily thyroxine and triiodothyronine, are tyrosine derived hormones synthesized by the thyroid gland through iodination of thyroglobulin. They require TH transporters to get into target cells, where they interact with specific nuclear TH receptors in the nucleus, TRα and TRβ, leading to changes in gene transcription of downstream targets. TH signaling is important for regulating stem cell niches in many tissues, including the brain. In the pituitary, TH’s primary established effect is its negative feedback on thyrotropes. However, postnatal pituitary stem cells also express the TH transporter, Slc16a2, suggesting that they are also TH-responsive. Yet, the role of TH in pituitary stem cell regulation is unknown.
We explored the prospective function of TH in postnatal pituitary stem cells through a published low-iodine diet (LID)-induced hypothyroidism mouse model. The LID includes 0.15% propylthiouracil (PTU), a drug which reduces TH production by inhibition of thyroperoxidase. Adult mice (8-12-weeks-old) were fed LID for four weeks to deplete systemic TH levels and hypothyroidism was confirmed by elevated pituitary Tshb mRNA expression. We performed scRNAseq on pooled pituitary cells collected from male and female mice fed control vs LID (3 mice per sex/diet combination). Loss of TH did not lead to major changes in the proportion of various hormone producing cell types and stem cells, including normal thyrotrope numbers. However, differential gene expression shows decreased Id2 expression in pituitary stem cells in both hypothyroid male and female mice.
Our data identified Id2 as a potential downstream target of TH in postnatal pituitary stem cells. ID proteins sequester other proteins such as basic helix-loop-helix transcription factors that drive differentiation, promoting cell stemness in many tissues. Id2 is expressed during pituitary development but its role has not been fully explored. Previous studies have shown that Id2 promotes pituitary tumor cell proliferation in Rb heterozygotes. Our finding suggests that TH may influence pituitary stem proliferative or differentiation potential through an Id2 mediated pathway.
We are currently working on a SOX2–ID2 immunohistochemistry (IHC) to validate our scRNA-seq findings. To further characterize the function of Id2 in pituitary stem cells, we will conduct co-immunoprecipitation assays for ID2. Additionally, we are investigating the effects of reduced Id2 expression using both a conditional knockout mouse model and a CRISPR-edited human embryonic stem cell (hESC) model. These studies will provide novel insights into the role of TH on pituitary stem cells both in the context of potential pharmacological targeting of pituitary stem cells as well as side effects of TH treatment on hypothyroid patients.

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