title: Human ZP3 restores fertility in Zp3 null mice without affecting order-specific sperm binding.
abstract: The mammalian zona pellucida surrounding ovulated eggs mediates sperm binding at fertilization, provides a postfertilization block to polyspermy, and facilitates passage of pre-implantation embryos down the oviduct. Although the three zona proteins (ZP1, ZP2, ZP3) are well conserved, mammalian fertilization is relatively specific and human sperm do not bind to the mouse zona pellucida. There are considerable in vitro data that ZP3 acts as a primary sperm adhesion molecule in mice and, by analogy, a similar role has been postulated for human ZP3. Genetically altered mice lacking ZP3 (Zp3(tm/tm)) do not form a zona pellucida and are infertile. To rescue this phenotype, transgenic mice expressing human ZP3 (67% identical to mouse ZP3) were produced and bred with Zp3(tm/tm) null mice. The resultant human ZP3 rescue females had chimeric zonae pellucidae composed of mouse ZP1, mouse ZP2 and human ZP3. Human ZP3 expressed in mouse oocytes had an apparent mass (64 kDa) indistinguishable from native human ZP3 and distinct from mouse ZP3 (83 kDa). Despite the presence of human ZP3, human sperm did not bind to the chimeric zona pellucida, and notwithstanding the absence of mouse ZP3, mouse sperm bound to ovulated eggs in vitro and fertility was restored in vivo. These data have implications regarding the molecular basis of mouse and human sperm binding to their respective zonae pellucidae.
authors.affiliation: Laboratory of Cellular and Developmental Biology, NIDDK, Developmental Endocrinology Branch, National Institutes of Health, Bethesda, MD, USA. tr44x@nih.gov
authors.forename: T L
authors.initials: TL
authors.lastname: Rankin
authors.forename: Z B
authors.initials: ZB
authors.lastname: Tong
authors.forename: P E
authors.initials: PE
authors.lastname: Castle
authors.forename: E
authors.initials: E
authors.lastname: Lee
authors.forename: R
authors.initials: R
authors.lastname: Gore-Langton
authors.forename: L M
authors.initials: LM
authors.lastname: Nelson
authors.forename: J
authors.initials: J
authors.lastname: Dean
mesh_terms: D000818:Animals; D002678:Chimera; D004527:Egg Proteins / Q000032:analysis* / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005298:Fertility / Q000235:genetics*; D005306:Fertilization; D006801:Humans; D007247:Infertility, Female / Q000235:genetics; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis* / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011956:Receptors, Cell Surface; D013084:Sperm-Ovum Interactions; D013094:Spermatozoa / Q000502:physiology; D015044:Zona Pellucida / Q000502:physiology* / Q000648:ultrastructure; D000072216:Zona Pellucida Glycoproteins
chemical_list: D004527:Egg Proteins; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C000606514:ZP1 protein, human; C000606515:ZP2 protein, human; C000606517:ZP3 protein, human; D000072216:Zona Pellucida Glycoproteins; C000606519:Zp1 protein, mouse; C000606520:Zp2 protein, mouse; C000606521:Zp3 protein, mouse