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Molecular and Cellular Biology, December 2000, p. 9337-9345, Vol. 20, No. 24
Institute for Molecular Biology and
Biotechnology1 and Department of
Biology,2 McMaster University, Hamilton,
Ontario, Canada L8S 4K1; Department of Cell Biology, University
of Virginia Health Sciences Center, Charlottesville, Virginia
229083; and Department of Pharmacology,
Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia,
Canada B3H 4H74
Received 7 July 2000/Returned for modification 29 August
2000/Accepted 27 September 2000
PEA3, a member of the Ets family of transcriptional regulatory
proteins, is expressed in a unique spatial and temporal pattern during
mouse embryogenesis; its overexpression is positively correlated with
HER2-mediated breast tumorigenesis in both humans and mice. To
determine whether PEA3 plays a part in development and oncogenesis and
to uncover its normal physiological role, we generated mice lacking
functional PEA3 by gene targeting in embryonic stem cells. PEA3
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Male Sexual Dysfunction in Mice Bearing Targeted
Mutant Alleles of the PEA3 ets Gene
/ mice arose from heterozygous crosses
with the expected Mendelian frequency, revealing that PEA3 is
dispensable for embryogenesis. PEA3 mutant mice displayed
no overt phenotype and lived a normal life span. However,
PEA3-deficient males failed to reproduce. PEA3 is expressed in several
male sexual organs, but gross and histological analyses of the organs
from PEA3/ mice revealed no abnormalities.
Spermatogenesis and spermiogenesis also appeared normal in mice
homozygous for the PEA3 mutation, and their sperm were
capable of fertilizing eggs in vitro. PEA3/
males engaged in normal mating behavior, but they did not set copulatory plugs and sperm could not be detected in the uteri of
females that had mated with PEA3/ males.
Erections could be evoked by abdominal pressure in PEA3-deficient male
mice, and the results of in vitro experiments revealed that the corpus
cavernosum isolated from PEA3 mutant males relaxed in
response to acetylcholine. Therefore, the infertility of
PEA3 mutant males involves either mechanisms proximal to
the cavernosal smooth muscle or an ejaculatory dysfunction. However,
PEA3 mutant mice are phenotypically distinguishable from
other knockout mice with such deficits and thus provide a unique model
for further investigation of male sexual dysfunction.
*
Corresponding author. Mailing address: Institute for
Molecular Biology and Biotechnology, McMaster University, 1280 Main St. W., Hamilton, Ontario, Canada L8S 4K1. Phone: (905) 525-9140, ext. 27217. Fax: (905) 521-2955. E-mail:
hassell{at}mcmaster.ca.
Molecular and Cellular Biology, December 2000, p. 9337-9345, Vol. 20, No. 24
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Copyright © 2000, American Society for Microbiology. All rights reserved.
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