Endocrine Abstracts

EGFR ligands, a family of seven related peptide growth factors, are emerging as key factors regulating different aspects of female reproduction including oocyte maturation and ovulation, and implantation. Betacellulin (BTC) is a rather neglected EGFR ligand whose biological activities have been mostly associated with the endocrine pancreas. During the routine breeding of recently established BTC transgenic mouse lines (Schneider et al., Endocrinology 146, 5237–5246, 2005), reduced female fertility became evident. Thus, a systematic study of different aspects of female reproduction was carried out. While puberty onset and estrous cyclicity were not affected in the transgenic animals, controlled matings revealed reduced litter size as the major reproductive deficit of BTC transgenic females (5.3±0.7 vs. 9.9±0.3 pups/litter in non-transgenic controls). Embryo implantation (visualized by injection of blue dye) was shown to be delayed. However, the number of embryos implanted or recovered from the uterus was already reduced by about 50% in the transgenic group, indicating that delayed implantation was not the cause of reduced litter size. Collection of oocytes from transgenic and control females mated to non-transgenic males revealed that the number of ovulated oocytes was not different between the groups (10.4 vs 10.7, respectively). However, the proportion of fertilized oocytes recovered from transgenic females was significantly reduced (54% vs. 81.7%). Next, in vitro maturation (IVM) and fertilization (IVF) were carried out to study these aspects more closely. While IVM rate was only slightly affected, the proportion of fertilized oocytes obtained from transgenic females was strongly reduced as compared to the rate observed in oocytes derived from the control group (57.5% vs 84.6% cleavage rate). Localization of strong transgene-derived BTC levels in the cumulus and granulosa cells of transgenic follicles supports this observation. In summary, excess of BTC perturbs oocyte maturation and fertilization. Implantation is delayed but appears to have no consequence for the overall reproductive performance of transgenic females.