Effect of thyroxine on DNA synthesis and thymidine kinase activity during cerebellar development

Abstract

Body growth, cerebellar growth, cerebellar DNA content, and cerebellar thymidine kinase activity were studied in rats made hyperthyroid from birth, and littermate controls. Hyperthyroidism caused the following. (1) Significantly decreased body weight in treated animals aged 3 days and older. (2) A significant decrease in cerebellar wet weight at age 12 days and later in treated animals. (3) A significant increase in cerebellar DNA by the age of 2 days in treate animals, continuing through the age of 6 days. By the age of 12 days, cerebellar DNA content was significantly decreased below control values in treated animals. (4) An induction of cerebellar thymidine kinase activity in treated animals by age 1 day continuing through age 5 days, with maximum elevation being 137% of control values at age 4 days. By age 9 days, cerebellar thymidine kinase activity in treated animals had fallen to levels significantly below control values and activity was minimal at age 15 days in comparison to disappearance of activity around age 18 days in cerebella of control animals. (5) DNA synthesis is thus accelerated in cerebella of thyroxine treated animals aged 2 to 6 days and subsequently total cerebellar DNA fails to reach normal values. Thymidine kinase activity in cerebella of treated animals is induced by age 1 day, prior to the increase of cerebellar DNA content in treated animals, and subsequently falls below control values by age 9 days, prior to a significant decrease in DNA below control values. This apparent shift to the left in the developmental spectrum of cerebellar thymidine kinase activity compared to the effects of thyroxine on DNA synthesis is discussed in the light of what is known about the effects of hormones on enzyme systems and possible mechanisms of action of thyroid hormones. The conclusions are drawn that thyroxine appears to induce thymidine kinase activity in early cerebellar development and appears to be related to premature decrease of enzyme activity. In addition, our findings support the possibility that thymidine kinase may be an essential regulatory enzyme in DNA biosynthesis, and that the effects on thymidine kinase and DNA biosynthesis of thyroxine in developing cerebellum may be secondary to a modulation of gene activity by the hormone.