title: Functional Consequences of Mannose and Asialoglycoprotein Receptor Ablation.
abstract: The mannose receptor (ManR, Mrc1) and asialoglycoprotein receptor (ASGR, Asgr1 and Asgr2) are highly abundant endocytic receptors expressed by sinusoidal endothelial cells and parenchymal cells in the liver, respectively. We genetically manipulated either receptor individually or in combination, revealing phenotypic changes in female and male mice associated with changes in circulating levels of many glycoproteins. Both receptors rise and fall in response to progesterone during pregnancy. Thirty percent of Asgr2(-/-) and 65% of Mrc1(-/-)Asgr2(-/-) mice are unable to initiate parturition at the end of pregnancy, whereas Mrc1(-/-) mice initiate normally. Twenty five percent of Mrc1(-/-)Asgr2(-/-) male mice develop priapism when mating due to thrombosis of the penile vein, but neither Mrc1(-/-) nor Asgr2(-/-) mice do so. The half-life for luteinizing hormone (LH) clearance increases in Mrc1(-/-) and Mrc1(-/-)Asgr2(-/-) mice but not in Asgr2(-/-) mice; however, LH and testosterone are elevated in all three knockouts. The ManR clears LH thus regulating testosterone production, whereas the ASGR appears to mediate clearance of an unidentified glycoprotein that increases LH levels. More than 40 circulating glycoproteins are elevated >3.0-fold in pregnant Mrc1(-/-)Asgr2(-/-) mice. Pregnancy-specific glycoprotein 23, undetectable in WT mice (<50 ng/ml plasma), reaches levels of 1-10 mg/ml in the plasma of Mrc1(-/-)Asgr2(-/-) and Asgr2(-/-) mice, indicating it is cleared by the ASGR. Elevation of multiple coagulation factors in Mrc1(-/-)Asgr2(-/-) mice may account for priapism seen in males. These male and female phenotypic changes underscore the key roles of the ManR and ASGR in controlling circulating levels of numerous glycoproteins critical for regulating reproductive hormones and blood coagulation.
authors.affiliation: From the Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: Yiling
authors.initials: Y
authors.lastname: Mi
authors.affiliation: From the Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: Marcy
authors.initials: M
authors.lastname: Coonce
authors.affiliation: From the Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: Dorothy
authors.initials: D
authors.lastname: Fiete
authors.affiliation: From the Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Steirer
authors.affiliation: From the Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Dveksler
authors.affiliation: From the Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: R Reid
authors.initials: RR
authors.lastname: Townsend
authors.affiliation: From the Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110 Baenziger@wustl.edu.
authors.forename: Jacques U
authors.initials: JU
authors.lastname: Baenziger
mesh_terms: D000818:Animals; D037263:Asialoglycoprotein Receptor / Q000235:genetics / Q000378:metabolism*; D001777:Blood Coagulation / Q000235:genetics; D005260:Female; D006023:Glycoproteins / Q000097:blood / Q000235:genetics; D007986:Luteinizing Hormone / Q000097:blood / Q000235:genetics; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D036801:Parturition / Q000097:blood / Q000235:genetics; D011247:Pregnancy; D011317:Priapism / Q000097:blood / Q000235:genetics / Q000473:pathology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D011971:Receptors, Immunologic; D013739:Testosterone / Q000097:blood / Q000235:genetics; D020246:Venous Thrombosis / Q000097:blood / Q000235:genetics / Q000473:pathology
chemical_list: D037263:Asialoglycoprotein Receptor; D006023:Glycoproteins; C581013:MRC1 protein, mouse; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D013739:Testosterone; D007986:Luteinizing Hormone
keywords: asialoglycoprotein receptor; carbohydrate function; carbohydrate-binding protein; gene knockout; glycobiology; glycoprotein clearance; mannose receptor; receptor structure-function; reproduction