The hypothyroid (hyt/hyt) mouse: a model system for studying the effects of thyroid hormone on developmental changes in gene expression.

Abstract

Thyroid hormone has been implicated as an important factor in rodent development. We have used a strain of mice with a recessive mutation producing congenital primary hypothyroidism (C.RF/J-hyt/+) to study the effects of thyroid hormone on developmental changes in the expression of genes encoding a number of proteins involved in lipid metabolism and transport. Total cellular RNA was prepared from the small intestine and liver of hyt/hyt mice and their unaffected littermates (+/?) at various times during postnatal development. RNA blots were probed with apolipoprotein A-I, A-II, A-IV, B, and E cDNAs plus cDNAs encoding the low density lipoprotein receptor, 3-hydroxy-3-methylglutaryl coenzyme A reductase, and three cytoplasmic hydrophobic ligand-binding proteins (two fatty acid-binding proteins and a protein that binds all-trans-retinol). Hypothyroidism results in small changes (1.5- to 5-fold) in the concentration of many of these mRNAs in liver and small intestine between postnatal days 15 and 50. A much greater tissue-specific effect was noted on apolipoprotein B (apoB) gene expression. In euthyroid +/? animals, apoB mRNA levels fall by a factor of 30 in liver between days 20 and 35 without a comparable decrease in the small intestine. This liver-specific decrease does not occur in hyt/hyt animals. The normal decrease in hepatic apoB mRNA levels is accompanied by a decrease in plasma apoB-100 but not apoB-48. No reduction in either form of plasma apoB was noted in hyt/hyt animals. Mutant hyt/hyt mice given thyroxine from birth to 35 days had liver apoB mRNA levels comparable to those in +/? littermates. In contrast, hepatic apoB mRNA concentrations did not fall to normal levels in hyt/hyt mice given thyroxine from postnatal days 15 to 35. All treatment groups have comparable levels of plasma corticosteroids. These data suggest that (i) there is a critical period or a required response time during postnatal development for thyroid hormone action on apoB gene expression, (ii) thyroid hormone's effect on apoB is tissue specific, and (iii) the hyt/hyt mouse represents a useful system to evaluate the developmental effects of thyroid hormone on specific gene expression.