title: Fetuin-B, a liver-derived plasma protein is essential for fertilization.
abstract: The zona pellucida (ZP) is a glycoprotein matrix surrounding mammalian oocytes. Upon fertilization, ZP hardening prevents sperm from binding to and penetrating the ZP. Here, we report that targeted gene deletion of the liver-derived plasma protein fetuin-B causes premature ZP hardening and, consequently, female infertility. Transplanting fetuin-B-deficient ovaries into wild-type recipients restores fertility, indicating that plasma fetuin-B is necessary and sufficient for fertilization. In vitro fertilization of oocytes from fetuin-B-deficient mice only worked after rendering the ZP penetrable by laser perforation. Mechanistically, fetuin-B sustains fertility by inhibiting ovastacin, a cortical granula protease known to trigger ZP hardening. Thus, plasma fetuin-B is necessary to restrain protease activity and thereby maintain ZP permeability until after gamete fusion. These results also show that premature ZP hardening can cause infertility in mice.
authors.affiliation: Helmholtz Institute for Biomedical Engineering, Biointerface Laboratory, 52074 Aachen, Germany.
authors.forename: Eileen
authors.initials: E
authors.lastname: Dietzel
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wessling
authors.forename: Julia
authors.initials: J
authors.lastname: Floehr
authors.forename: Cora
authors.initials: C
authors.lastname: Schäfer
authors.forename: Silke
authors.initials: S
authors.lastname: Ensslen
authors.forename: Bernd
authors.initials: B
authors.lastname: Denecke
authors.forename: Benjamin
authors.initials: B
authors.lastname: Rösing
authors.forename: Joseph
authors.initials: J
authors.lastname: Neulen
authors.forename: Thomas
authors.initials: T
authors.lastname: Veitinger
authors.forename: Marc
authors.initials: M
authors.lastname: Spehr
authors.forename: Tanja
authors.initials: T
authors.lastname: Tropartz
authors.forename: René
authors.initials: R
authors.lastname: Tolba
authors.forename: Thomas
authors.initials: T
authors.lastname: Renné
authors.forename: Angela
authors.initials: A
authors.lastname: Egert
authors.forename: Hubert
authors.initials: H
authors.lastname: Schorle
authors.forename: Yuliya
authors.initials: Y
authors.lastname: Gottenbusch
authors.forename: André
authors.initials: A
authors.lastname: Hildebrand
authors.forename: Irene
authors.initials: I
authors.lastname: Yiallouros
authors.forename: Walter
authors.initials: W
authors.lastname: Stöcker
authors.forename: Ralf
authors.initials: R
authors.lastname: Weiskirchen
authors.forename: Willi
authors.initials: W
authors.lastname: Jahnen-Dechent
mesh_terms: D000818:Animals; D002463:Cell Membrane Permeability; D004624:Embryo Transfer / Q000379:methods; D004622:Embryo, Mammalian / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation; D005260:Female; D005306:Fertilization; D005307:Fertilization in Vitro; D060752:Fetuin-B / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D007247:Infertility, Female / Q000378:metabolism / Q000473:pathology; D008297:Male; D045726:Metalloproteases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009865:Oocytes / Q000378:metabolism / Q000473:pathology; D010053:Ovary / Q000378:metabolism / Q000637:transplantation; D011247:Pregnancy; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D013094:Spermatozoa / Q000378:metabolism / Q000502:physiology; D015044:Zona Pellucida / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*
chemical_list: C504688:Fetub protein, mouse; D060752:Fetuin-B; D011994:Recombinant Proteins; C487827:Astl protein, mouse; D045726:Metalloproteases