Ablation of GalNAc-4-sulfotransferase-1 enhances reproduction by altering the carbohydrate structures of luteinizing hormone in mice
- 1 April 2008
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 118 (5), 1815-1824
- https://doi.org/10.1172/jci32467
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.Keywords
This publication has 66 references indexed in Scilit:
- Phenotypic characterisation of mice with exaggerated and missing LH/hCG actionMolecular and Cellular Endocrinology, 2007
- Differential expression and enzymatic properties of GalNAc-4-sulfotransferase-1 and GalNAc-4-sulfotransferase-2Glycobiology, 2005
- Overexpression of Human Chorionic Gonadotropin Causes Multiple Reproductive Defects in Transgenic Mice1Biology of Reproduction, 2003
- Acyline: The First Study in Humans of a Potent, New Gonadotropin-Releasing Hormone AntagonistJournal of Clinical Endocrinology & Metabolism, 2002
- Perspective: The Importance of Genetic Defects in Humans in Elucidating the Complexities of the Hypothalamic-Pituitary-Gonadal AxisEndocrinology, 2001
- Molecular Cloning and Expression of anN-Acetylgalactosamine-4-O-sulfotransferase That Transfers Sulfate to Terminal and Non-terminal β1,4-LinkedN-AcetylgalactosaminePublished by Elsevier BV ,2001
- Elevated Luteinizing Hormone in Prepubertal Transgenic Mice Causes Hyperandrogenemia, Precocious Puberty, and Substantial Ovarian PathologyEndocrinology, 1997
- Gonadotropin-Releasing Hormone Antagonists: Novel Members of the Azaline B FamilyJournal of Medicinal Chemistry, 1995
- Molecular basis of the specificity of binding of glycoprotein hormones to their receptorsEndocrine Reviews, 1992
- Pituitary glycoprotein hormone oligosaccharides: Structure, synthesis and function of the asparagine-linked oligosaccharides on lutropin, follitropin and thyrotropinBiochimica et Biophysica Acta (BBA) - Reviews on Biomembranes, 1988