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 10

LH from GalNAc-4-ST1–/– mice has increased levels of Siaα2,6GalNAc.

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LH from GalNAc-4-ST1–/– mice has increased levels of Siaα2,6GalNAc. ...
Extracts were prepared from 5 WT and 5 GalNAc-4-ST1–/– mice that had not been castrated (A and B) or had been castrated (cast) (C–F). Identical aliquots of each extract were incubated with immobilized WFA or SNA-1, which binds structures terminating with GalNAc or Siaα2,6GalNAc, respectively. Terminal sialic acid was removed by digestion with neuraminidase as indicated prior to incubation with WFA or SNA-1 (B, D, and F). Equal aliquots of the starting material (In), the unbound fraction (Ub), and the fractions selectively eluted with GalNAc or lactose (Elution) were analyzed by SDS-PAGE and Western blotting with anti-LHβ. (A) Binding of pituitary extracts by WFA-agarose. (B) Binding of pituitary extracts by WFA-agarose following neuraminidase digestion. (C) Binding of pituitary extracts from castrated mice by WFA-agarose. (D) Binding of pituitary extracts from castrated mice by WFA-agarose following neuraminidase digestion. (E) Binding by SNA-1–agarose. (F) Binding by SNA-1–agarose following digestion with neuraminidase.