Abstract
Congenital hypothyroidism is a genetic condition in which the thyroid gland fails to produce sufficient thyroid hormone (TH), resulting in metabolic dysfunction and growth retardation. Xb130−/− mice exhibit perturbations of thyrocyte cytoskeleton and polarity, and develop postnatal transient growth retardation due to congenital hypothyroidism, leading ultimately to multinodular goiter. To determine the underlying mechanisms, we performed transcriptomic analyses on thyroid glands of mice at three age points: week 2 (W2, before visible growth retardation), W4 (at the nadir of growth); and W12 (immediately before full growth recovery). Using gene set enrichment analysis, we compared a defined set of thyroidal genes between Xb130+/+ and Xb130−/− mice to identify differentially enriched gene clusters. At the earliest postnatal stage (W2), the thyroid glands of Xb130−/− mice exhibited significantly downregulated gene clusters related to cellular metabolism, which continued to W4. Additionally, mutant thyroids at W4 and W12 showed upregulated gene clusters related to extracellular matrix, angiogenesis, and cell proliferation. At W12, despite nearly normal levels of serum TH and TSH and body size, a significantly large number of gene clusters related to inflammatory response were upregulated. Early postnatal TH deficiency may suppress cellular metabolism within the thyroid gland itself. Upregulation of genes related to extracellular matrix and angiogenesis may promote subsequent thyroid growth. Chronic inflammatory responses may contribute to the pathogenesis of multinodular goiter in later life. Some of the pathoadaptive responses of Xb130−/− mice may overlap with those from other mutations causing congenital hypothyroidism.
Highlights
The thyroid gland synthesizes and releases thyroid hormone (TH), essential for promoting cellular metabolism, tissue function, and body growth
We found that most of the gene clusters downregulated at W2 and W4 in thyroid glands of Xb130−/− mutant mice are related to mitochondrial energetics, including the coenzyme metabolic process (Figure 4a), as well as lipid catabolic process and fatty acid metabolism (Figure 4b), indicating reduced utilization of glucose and fatty acids for cellular metabolism
While congenital hypothyroidism delays the growth of the whole body, the thyroid gland suffers from impaired cellular metabolism that seems to suggest the effect of insufficient TH on the thyroid gland itself
Summary
The thyroid gland synthesizes and releases thyroid hormone (TH), essential for promoting cellular metabolism, tissue function, and body growth. Causes of deficient TH synthesis include thyroid gland maldevelopment (dysgenesis), followed by genetic defects in TH synthesis [2–4]. Both thyroid gland development and the function of gene products involved in TH synthesis are critically dependent upon the development and maintenance of thyroid epithelial polarity. XB130, known as actin filament-associated protein 1-like 2 (AFAP1L2) [7], is predominantly expressed in the thyroid gland [7–9]. This adaptor protein, which localizes in the cytoplasm and is enriched at the apical plasma membrane, plays a crucial role in defining thyroid polarity and cytoskeletal architecture [10]. Older Xb130−/− mice develop multinodular goiter (MNG), characterized by an enlarged thyroid gland with focal degeneration resulting in nodule formation [12], indicating age-related response(s) to the genetic defects of the thyrocyte cytoskeleton, early thyroid gland development plus accompanying TH synthesis defects
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