HUMAN ZP3 RESTORES FERTILITY IN ZP3 NULL MICE WITHOUT AFFECTING ORDER-SPECIFIC SPERM BINDING

The mammalian zona pellucida surrounding ovulated eggs mediates sperm binding at fertilization, provides a postfertilization block to polysp ermy, and facilitates passage of pre-implantation embryos down the ovi duct, Although the three zona proteins (ZP1, ZP2, ZP3) are well conser ved, 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, Genetica lly altered mice lacking ZP3 (Zp3(tm/tm)) do not form a zona pellucida and are infertile, To rescue this phenotype, transgenic mice expressi ng human ZP3 (67% identical to mouse ZP3) were produced and bred with Zp3(tm/tm) null mice. The resultant human ZP3 rescue females had chime ric zonae pellucidae composed of mouse ZP1, mouse ZP2 and human ZP3, H uman ZP3 expressed in mouse oocytes had an apparent mass (64 kDa) indi stinguishable from native human ZP3 and distinct from mouse ZP3 (83 kD a). 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 restor ed in vivo. These data have implications regarding the molecular basis of mouse and human sperm binding to their respective zonae pellucidae .