Ovarian development in mice bearing homozygous or heterozygous null mutations in zona pellucida glycoprotein gene mZP3

Abstract

The plasma membrane of all mammalian eggs is surrounded by a thick extracellular coat, the zonu pellirc.id(i (ZP), whose paramount function is to regulate species-specific fertilization. The mouse egg ZP is composed of only three glycoproteins, mZPI -3, that are synthesized and secreted exclusively by oocytes during their 2-3 week growth phase. Disruption of the rnZP3 gene by targeted mutagenesis in embryonic stem (ES) cells yields mice heterozygous ( r n ~ P 3 + / -o)r hornozygous ( r n ~ P 3 - / -f)o r the null mutation. As expected, male mice bearing the null mutation are indistinguishable from wild-type males with respect to viability and fertility. Female m ~ ~ 3 +m/ic-e are as fertile as wild-type animals, but their eggs have a thin ZP (-2.7 pm thick) as compared to the ZP (-6.2 pm thick) of eggs from wild-type animals. On the other hand, female rn~P3-/m- ice are infertile and their eggs lack a ZP. The infertility apparently is due to the lack of a sufficient number of eggs in oviducts of superovulated ~ZPJ-lfemales. Light micrographs reveal that development of ovarian follicles is often retarded in rnz~3- l -m ice as compared to wild-type animals. This is manifested as reduced ovarian weights, reduced numbers of Graafian follicles, and reduced numbers of fully-grown oocytes in I ~ Z P ~ -f/em- ales. I t seems likely that the pleiotropic effects of the homozygous null mutation on ovarian development may be due, at least in part, to disruption of intercellular communication between growing oocytes and their surrounding follicle cells.