TARGETED MUTATION IN BETA-1,4-GALACTOSYLTRANSFERASE LEADS TO PITUITARY INSUFFICIENCY AND NEONATAL LETHALITY

Despite much attention, the function of oligosaccharide chains on glyc oproteins and glycolipids remains largely unknown. Our understanding o f oligosaccharide function in vivo has been limited to the use of reag ents and targeted mutations that eliminate entire classes of oligosacc haride chains. However, most biological functions for oligosaccharides have been attributed to specific terminal sequences on these glycosid e chains; yet, there have been few studies that examine the consequenc es of modifying terminal oligosaccharide structures in vivo. To addres s this issue, mice were created bearing a targeted mutation in beta 1, 4-galactosyltransferase (GalTase), an enzyme responsible for elaborati on of many of the proposed biologically active carbohydrate epitopes. Most GalTase-null mice died within the first few weeks after birth and were characterized by stunted growth, thin skin, sparse hair, and deh ydration. In addition, spermatogenesis was delayed, the lungs were poo rly developed, and the adrenal cortices were poorly stratified. The fe w surviving adults had puffy skin (myxedema) and difficulty delivering pups at birth (dystocia) and failed to lactate (agalactosis). All of these defects are consistent with endocrine insufficiency, which was c onfirmed by markedly decreased levels of serum thyroxine. The polyglan dular nature of the endocrine insufficiency is indicative of a failure of the anterior pituitary gland to stimulate the target endocrine org ans. Previous in vitro studies have suggested that incomplete glycosyl ation of anterior pituitary hormones leads to the creation of hormone antagonists, which down-regulate subsequent endocrine function, produc ing polyglandular endocrine insufficiency. In GalTase-null mice, the a nterior pituitary acquired a normal secretory phenotype during neonata l development indicative of normal glycoprotein hormone synthesis and secretion. However, as expected, the gland was devoid of GalTase activ ity. These results support a requirement for terminal oligosaccharide sequences for anterior pituitary hormone function. The fact that simil ar to 10% of the GalTase-null mice survive the neonatal period indicat es the presence of a previously unrecognized compensatory pathway for glycoprotein hormone glycosylation and/or action. (C) 1997 Academic Pr ess.