Ablation of GalNAc-4-sulfotransferase-1 enhances reproduction by altering the carbohydrate structures of luteinizing hormone in mice
Yiling Mi, … , Dorothy Fiete, Jacques U. Baenziger
Yiling Mi, … , Dorothy Fiete, Jacques U. Baenziger
Published April 22, 2008
Citation Information: J Clin Invest. 2008;118(5):1815-1824. https://doi.org/10.1172/JCI32467.
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Research Article Reproductive biology

Ablation of GalNAc-4-sulfotransferase-1 enhances reproduction by altering the carbohydrate structures of luteinizing hormone in mice

Abstract

Luteinizing hormone (LH), produced in the anterior lobe of the pituitary, is a member of the hypothalamic-pituitary-gonad axis that is required for production of the sex hormones estradiol, progesterone, and testosterone. Perturbations in levels of hormones associated with this axis can result in defects in sexual development and maturity. LH bears unique N-linked carbohydrate units that terminate with a sulfated N-acetylgalactosamine structure (GalNAc-4-SO4) that mediates its clearance from the blood. To determine the significance of this terminal structure, we ablated the gene encoding the sulfotransferase responsible for sulfate addition to GalNAc on LH, GalNAc-4-sulfotransferase-1 (GalNAc-4-ST1) in mice. Mice lacking GalNAc-4-ST1 exhibited increased levels of circulating LH. In male mice, this resulted in elevated levels of testosterone and precocious maturation of testis and seminal vesicles. Female mice lacking GalNAc-4-ST1 demonstrated elevated estrogen levels and exhibited precocious sexual maturation and increased fecundity. Female mice remained in estrus for prolonged periods and produced almost 50% more litters per mouse than wild-type mice over the same period of time. Thus, sulfate modification of the terminal glycosylation of LH plays a central role in regulating the hypothalamic-pituitary-gonad axis in vivo.

Authors

Yiling Mi, Dorothy Fiete, Jacques U. Baenziger

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Figure 9

Clearance of endogenous LH in WT and GalNAc-4-ST1–/– mice.

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Clearance of endogenous LH in WT and GalNAc-4-ST1–/– mice. WT and Ga...
WT and GalNAc-4-ST1–/– 36-week-old mice were surgically castrated or ovariectomized 5 days prior to the clearance studies. Serum was taken from the WT (n = 8) and GalNAc-4-ST1–/– (n = 8) castrated male mice and from the WT (n = 9) and GalNAc-4-ST1–/– (n = 6) ovariectomized female mice at the initiation of the clearance study. Acyline (10 μg/mouse) was administered intravenously, and blood was withdrawn at 5, 10, 20, and 30 minutes following introduction of acyline. (A) Comparison of LH clearance by individual castrated WT (squares) and castrated GalNAc-4-ST1–/– (triangles) mice following acyline injection. Half-lives for a total of 17 WT and 14 GalNAc-4-ST1–/– mice were determined using GraphPad Prism 4.0. (B) LH removed from the blood of WT mice had a half-life of 7.2 minutes (SEM = 0.6), and LH removed from the blood of GalNAc-4-ST1–/– mice had a half-life of 10.1 minutes (SEM = 0.9). The difference in half-lives is significant: *P = 0.01.