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This Article Full Text Full Text (PDF) All Versions of this Article: 78/1/43    most recent biolreprod.107.062588v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Gratao, A. A Articles by Schneider, M. R Search for Related Content PubMed PubMed Citation Articles by Gratao, A. A Articles by Schneider, M. R Agricola Articles by Gratao, A. A Articles by Schneider, M. R

Betacellulin Overexpression in the Mouse Ovary Leads to MAPK3/MAPK1 Hyperactivation and Reduces Litter Size by Impairing Fertilization¹

Institute of Molecular Animal Breeding and Biotechnology³ and Laboratory for Functional Genome Analysis (LAFUGA),⁴ Gene Center of the Ludwig-Maximilians University, 81377 Munich, Germany Institute of Veterinary Anatomy,⁵ Ludwig-Maximilians University, 80539 Munich, Germany

ABSTRACT

The epidermal growth factor receptor (EGFR) and its ligands are emerging as key molecules in regulating female reproduction. Here, we used a transgenic mouse model to evaluate whether and at which level of the reproduction cascade higher-than-normal levels of the EGFR ligand betacellulin (BTC) in the reproductive organs affect fertility. Western blots and immunohistochemistry revealed increased BTC levels in uterus and ovaries from transgenic females, particularly evident in granulosa cells of antral follicles. Onset of puberty, estrous cyclicity, and the anatomy and histology of reproductive organs at puberty were not altered as compared to control females. Fertility tests revealed a reduction (50%) in litter size as the major reproductive deficit of transgenic females. Embryo implantation was delayed in transgenic females, but this was not the reason for the reduced litter size. Transgenic females produced a normal number of oocytes after natural ovulation. The in vivo fertilization rate was significantly reduced in untreated transgenic females but returned to normal levels after superovulation. Impaired oocyte fertilization in the absence of superovulation treatment was associated with MAPK3/MAPK1 hyperactivation in BTC transgenic ovaries, whereas similar levels of MAPK3/MAPK1 activation were detected in transgenic and control ovaries after superovulation treatment. Thus, tight regulation of MAPK3/MAPK1 activity appears to be essential for appropriate granulosa cell function during oocyte maturation. Our study identified hitherto unknown effects of BTC overabundance in reproduction and suggests BTC as a novel candidate protein for the modulation of fertility.

betacellulin, EGFR, female reproductive tract, fertilization, growth factors, implantation, MAPK3/MAPK1, transgenic mice, uterus

¹Supported in part by the Deutsche Forschungsgemeinschaft (FOR 478, GRK 1029). A.A.G. is a recipient of a fellowship from the CAPES, Brazil.

Correspondence: ²Marlon R. Schneider, Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians University, Feodor-Lynen-Str. 25, 81377 Munich, Germany. FAX: 49 89 218076849; e-mail: schnder{at}lmb.uni-muenchen.de