Evaluation and characterization of the hyt/hyt hypothyroid mouse: II. Abnormalities of TSH and the thyroid gland

The hyt/hyt mouse (BALB/cBY-hYt, ChytRF) provides a useful model for exploring the effect of inherited severe primary hypothyroidism. Studies were undertaken to try to define the basis of the primary hypothyroidism in mice homozygous for the autosomal recessive gene, hyt. These mice had congenital hypothyroidism of fetal onset after 15 days post conception. Through their lifetime, the hyt/hyt mice had reduced serum thyroxine (T₄), triiodothyronine (T₃), reduced thyroid gland intralumenal colloid on electron microscopy and a 100-fold elevation of TSH-like activity compared to hyt/+ littermales. Thyroglohulin made in hyt/hyt animals was similar in size to normal thyroglohulin which was inconsistent with a major structural thyroglohulin gene defect. The thyroglobulin was iodinated. Marked, erratic dilation of rough endoplasmic reticulum (RER) was noted in hyt/hyt mouse follicular cells. Despite these ultrastructural findings, pulse chase and immunoprecipitalion studies with isolated hyt/hyt and normal thyroid glands indicated that normal thyroglobulin processing occurred in the RfcR and Golgi of the hyt/hyt mice. The hyt/hyt thyroid glands were hypoplastic compared to hyt/ + littermales. Histologically, the hyt'hyi thyroid glands demonstrated an increase in smaller follicular cells, and greater variability in follicular size compared to hyt/ + littermates. Histological and ultrastructural abnormalities in the gland were similar to those seen in certain cases of human congenital hypothyroidism with TSH receptor insensitivity of the thyroid gland. These findings along with the significant TSH elevation, the reduction in colloid and in serum T₃ and T₄. the efficacy of the hypothalamo-pituitary-thyroid feedback system, and previous observations of reduced iodine uptake and intra thyroidal T₃ [3] suggested that primary hypothyroidism in the hyt/hyt mouse might be due to a defect in TSH responsivity of the thyroid gland.