Thyroid hormone synthesis continues despite biallelic thyroglobulin mutation with cell death

Abstract

Thyroxine synthesis from dead cellsComplete absence of thyroid hormone is incompatible with life in vertebrates. Thyroxine is synthesized within thyroid follicles upon iodination of thyroglobulin conveyed from the endoplasmic reticulum (ER), via the Golgi complex, to the extracellular follicular lumen.In congenital hypothyroidism from bi-allelic thyroglobulin mutation, thyroglobulin is misfolded and cannot advance from the ER, eliminating its secretion and triggering ER stress. Nevertheless, untreated patients somehow continue to synthesize sufficient thyroxine to yield measurable serum levels that sustain life.We demonstrate that TG W2346R/ W2346R humans, TG cog/cog mice, and TG rdw/rdw rats exhibit no detectable ER export of thyroglobulin, accompanied by severe thyroidal ER stress and thyroid cell death.Nevertheless, thyroxine is synthesized and brief treatment of TG rdw/rdw rats with anti-thyroid drug is lethal to the animals. When untreated, remarkably, thyroxine is synthesized on the mutant thyroglobulin protein, delivered via dead thyrocytes that decompose within the follicle lumen, where they are iodinated and cannabilized by surrounding live thyrocytes. As the animals continue to grow a goiter, circulating thyroxine increases. However, when TG rdw/rdw rats age, they cannot sustain goiter growth that provides the dying cells needed for ongoing thyroxine synthesis, resulting in profound hypothyroidism. These results establish a disease mechanism wherein dead thyrocytes support organismal survival.

Thyroidal Transcriptomic Profiles of Pathoadaptive Responses to Congenital Hypothyroidism in XB130 Knockout Mice

“…Subsequently, after the nadir of growth, the thyroid gland begins to enlarge under TSH stimulation with upregulated genes related to ECM, cell proliferation and angiogenesis. These data support recent studies demonstrating that thyroid gland growth is needed to help to alleviate TH deficiency in congenital hypothyroidism [21], and this can eventually help to reverse the reduction in cellular metabolism in the thyroid gland and throughout the body.…”

Maintaining the thyroid gland in mutant thyroglobulin–induced hypothyroidism requires thyroid cell proliferation that must continue in adulthood

“…While all three tissues exhibited prominent eosinophilic staining consistent with accumulation of Tg protein, in WT ( TG +/+ ) thyroid, the Tg protein was primarily localized extracellularly in the follicle lumen, whereas in TG rdw/rdw and TG cog/cog mouse thyroid glands, most Tg proteins were found in an expanded and a distorted cytoplasm within the thyrocytes ( Fig. 2 A ), although there was some aberrant material in the follicle lumen (that we have recently established is comprised of the detritus of dead cells ( 21 )). From multiple images of thyroid sections derived from 3-month-old animals of each genotype, the cross-sectional area of individual thyrocytes was abnormally expanded approximately eightfold in TG rdw/rdw and TG cog/cog mouse thyroid glands ( Fig.…”

“…Because both TG cog/cog mice and WIC- TG rdw/rdw rats are known to exhibit intrathyroidal cell death ( 21 ), we performed TUNEL staining on the newly engineered TG rdw/rdw mice. As expected, the thyroid glands of TG rdw/rdw mice revealed 4′,6-diamidino-2-phenylindole (DAPI; Invitrogen)–positive nuclear material within the lumen of thyroid follicles, associated with positive TUNEL staining ( Fig.…”

“…We recently reported that in WIC rats, TG rdw/rdw homozygotes do begin to develop thyroid enlargement within the first two postnatal months, but their absence of goiter in adulthood involves an inability to maintain the goiter as a function of aging ( 21 ). As TG cog/cog mice exhibit thyroid cell death ( Fig.…”

“…On the one hand, primary hypothyroidism with reduced circulating thyroid hormone levels results in a compensatory upregulation of the pituitary secretion of thyroid stimulating hormone (TSH) to induce hyperplastic ( i.e. , proliferative) thyroid gland growth ( 16 , 17 , 18 , 19 , 20 ); on the other hand, the ER stress caused by misfolded mutant Tg has been found to be associated with thyroid cell death in both animal models and human patients ( 21 ). Indeed, we recently demonstrated that, albeit inefficient, T 4 can be synthesized on mutant Tg released in the follicle lumen from dead thyrocytes, and thyroid goiter growth (proliferation in excess of cell death) helps to provide the cells that sustain this mechanism ( 21 ).…”