OVARIAN DEVELOPMENT IN MICE BEARING HOMOZYGOUS OR HETEROZYGOUS NULL MUTATIONS IN ZONA-PELLUCIDA GLYCOPROTEIN GENE MZP3

The plasma membrane of all mammalian eggs is surrounded by a thick ext racellular coat, the zona pellucida (ZP), whose paramount function is to regulate species-specific fertilization. The mouse egg ZP is compos ed of only three glycoproteins, mZP1-3, that are synthesized and secre ted exclusively by oocytes during their 2-3 week growth phase. Disrupt ion of the mZP3 gene by targeted mutagenesis in embryonic stem (ES) ce lls yields mice heterozygous (mZP3(+/-)) or homozygous (mZP3(-/-)) for the null mutation. As expected, male mice bearing the null mutation a re indistinguishable from wild-type males with respect to viability an d fertility. Female mZP3(+/-) mice are as fertile as wild-type animals , but their eggs have a thin ZP (similar to 2.7 mu m thick) as compare d to the ZP (similar to 6.2 mu m thick) of eggs from wild-type animals . On the other hand, female mZP3(-/-) mice are infertile and their egg s lack a ZP. The infertility apparently is due to the lack of a suffic ient number of eggs in oviducts of superovulated mZP3(-/-) females. Li ght micrographs reveal that development of ovarian follicles is often retarded in mZP3(-/-) mice as compared to wild-type animals. This is m anifested as reduced ovarian weights, reduced numbers of Graafian foll icles, and reduced numbers of fully-grown oocytes in mZP3(-/-) females . It seems likely that the pleiotropic effects of the homozygous null mutation on ovarian development may be due, at least in part, to disru ption of intercellular communication between growing oocytes and their surrounding follicle cells.