Female infertility in grt mice is caused by thyroid hormone deficiency, not by insufficient TPST2 activity in the reproductive organs.

The growth-retarded (grt) mouse has an autosomal recessive hypothyroidism and the female shows lifelong infertility. We previously reported that these mutant phenotypes are caused by a deficiency in the enzymatic activity of tyrosylprotein sulfotransferase-2 (TPST2), and severe thyroid hypogenesis and consequent dwarfism are mainly due to the impairment of the tyrosine sulfation of thyroid-stimulating hormone receptor (TSHR) by TPST2. Although TPST2 is ubiquitously expressed and many proteins are predicted to be tyrosine sulfated and involved in many biological processes, the functional roles of tyrosine sulfation in the reproductive organs remain unclear. These findings tempted us to hypothesize two possible mechanisms underlying the infertility; a deficiency in TPST2 activity in the reproductive organs might cause the infertility in grt mice, or a significant decrease in serum thyroid hormones might impair the normal development of reproductive organs. When mutant female mice were fed a diet supplemented with sufficient thyroid powder to correct their growth retardation, the rate of copulation, pregnancy, and parturition was completely restored. Therefore, we concluded that the infertility in grt female is due to a thyroid hormone deficiency.