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 hypothalamicpituitary-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-SO 4 ) 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.

Modulation of Mannose and Asialoglycoprotein Receptor Expression Determines Glycoprotein Hormone Half-life at Critical Points in the Reproductive Cycle

“…Changes in the amount of ManR and ASGR expressed in the liver have the potential to alter the rate of clearance of ligands bearing recognized glycans from the blood. The circulatory half-life of endogenous LH in mice that have had their GalNAc-4-ST1 ablated increases from 7 to 10 min due to the addition of ␣2,6-linked sialic acid to the GalNAc in place of SO 4 (28). This form of LH is more potent, resulting in increased production of estrogen in females and testosterone in males.…”

“…Ablation of GalNAc-4-sulfotransferase-1 (GalNAc-4-ST1, CHST8) prevents the addition of SO 4 to LH glycans resulting in modification with ␣2,6-linked sialic acid to form Sia␣2,6GalNAc␤1,4GlcNAc␤1,2Man. Following GalNAc-4-ST1 ablation LH half-life is increased, testosterone and estrogen levels are increased, sexual maturation is precocious, and seminal vesicles and uteri are enlarged, indicating that LH is more potent due to its extended half-life (28).…”

Peptide-specific Transfer of N-Acetylgalactosamine to O-Linked Glycans by the Glycosyltransferases β1,4-N-Acetylgalactosaminyl Transferase 3 (β4GalNAc-T3) and β4GalNAc-T4

“…In the case of LH, the structural features of the LacdiNAc determine the circulatory half-life of the hormone following its release into the circulation, and as a result, its potency in vivo (22,23,36). SO 4 -4-GalNAc␤1, 4GlcNAc␤ is recognized by the N-terminal Cys-rich domain of the mannose receptor in its dimeric form (18,19,21,23), whereas NeuNAc␣2,6GalNAc␤1,4GlcNAc␤ is recognized by the asialoglycoprotein receptor (24).…”

Genetics and pathophysiology of mammalian sulfate biology

“…Endocrine disruption has also been linked to Chst8 in mice, which exhibits increased sex hormones, testosterone and luteinizing hormone (LH) (Mi et al, 2008b). These hormonal disturbances cause precocious sexual maturation and an increase in litter numbers and fecundity.…”

“…These hormonal disturbances cause precocious sexual maturation and an increase in litter numbers and fecundity. Chst8 is highly expressed in the pituitary gland and the disturbance of this sulfotransferase leads to increased levels of non-sulfonated LH (the active form of LH), which up-regulates the hypothalamic-pituitary-gonad axis via increased testosterone and estrogen levels in male and female mice, respectively (Mi et al, 2008a).…”