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Betacellulin Overexpression in the Mouse Ovary Leads to MAPK3/MAPK1 Hyperactivation and Reduces Litter Size by Impairing Fertilization
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 th...
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Published in: | Biology of reproduction 2008-01, Vol.78 (1), p.43-52 |
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Main Authors: | , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Online Access: | Get full text |
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Summary: | 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 (â¼50%) 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. |
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ISSN: | 0006-3363 1529-7268 |
DOI: | 10.1095/biolreprod.107.062588 |