Brca1 Mutations Enhance Mouse Reproductive Functions by Increasing Responsiveness to Male-Derived Scent.
We compared the gene expression profiles of ovarian granulosa cells harboring either mutant or wild type Brca1 to follow up on our earlier observation that absence of a functional Brca1 in these important regulators of menstrual/estrous cycle progression leads to prolongation of the pre-ovulatory phase of the estrous cycle and to increased basal levels of circulating estradiol. Here we show that ovarian granulosa cells from mice carrying a conditional Brca1 gene knockout express substantially higher levels of olfactory receptor mRNA than granulosa cells from wild type littermates. This led us to hypothesize that reproductive functions in mutant female mice might be more sensitive to male-derived scent than in wild type female mice. Indeed, it is well established that isolation from males leads to complete cessation of mouse estrous cycle activity while exposure to olfactory receptor ligands present in male urine leads to resumption of such activity. We found that Brca1-/- female mice rendered anovulatory by unisexual isolation resumed ovulatory activity more rapidly than their wild type littermates when exposed to bedding from cages where males had been housed. The prime mediator of this increased responsiveness appears to be the ovary and not olfactory neurons. This conclusion is supported by the fact that wild type mice in which endogenous ovaries had been replaced by Brca1-deficient ovarian transplants responded to male-derived scent more robustly than mutant mice in which ovaries had been replaced by wild type ovarian transplants. Our findings not only have important implications for our understanding of the influence of olfactory signals on reproductive functions, but also provide insights into mechanisms whereby genetic risk factors for breast and extra uterine Müllerian carcinomas may influence menstrual activity in human, which is itself an independent risk factor for these cancers.
Department of Pathology, University of Southern California Los Angeles, Los Angeles, California, United States of America.
Ying
Y
Liu
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
Malcolm C
MC
Pike
Department of Biochemistry and Molecular Biology, University of Southern California Los Angeles, Los Angeles, California, United States of America.
Nancy
N
Wu
Department of Obstetrics and Gynecology, University of Southern California Los Angeles, Los Angeles, California, United States of America.
Yvonne G
YG
Lin
Department of Obstetrics and Gynecology, University of Southern California Los Angeles, Los Angeles, California, United States of America.
Sara
S
Mucowski
USC Norris Comprehensive Cancer Center Bioinformatics Core and Division of Hematology, University of Southern California Los Angeles, Los Angeles, California, United States of America.
Vasu
V
Punj
Department of Pathology, University of Southern California Los Angeles, Los Angeles, California, United States of America.
Yuan
Y
Tang
Department of Biochemistry and Molecular Biology, University of Southern California Los Angeles, Los Angeles, California, United States of America.
Hai-Yun
HY
Yen
Department of Obstetrics and Gynecology, University of Southern California Los Angeles, Los Angeles, California, United States of America.
Frank Z
FZ
Stanczyk
Department of Pathology, University of Southern California Los Angeles, Los Angeles, California, United States of America.
Elena
E
Enbom
Department of Pathology, University of Southern California Los Angeles, Los Angeles, California, United States of America.
Theresa
T
Austria
Department of Women's Cancer, University College, London, United Kingdom.
Martin
M
Widschwendter
Department of Biochemistry and Molecular Biology, University of Southern California Los Angeles, Los Angeles, California, United States of America.
Robert
R
Maxson
Department of Pathology, University of Southern California Los Angeles, Los Angeles, California, United States of America.
Louis
L
Dubeau
D000818:Animals; D019313:BRCA1 Protein; D015153:Blotting, Western; D002478:Cells, Cultured; D005260:Female; D006107:Granulosa Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009812:Odorants; D010053:Ovary / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018035:Receptors, Odorant / Q000235:genetics / Q000378:metabolism*; D012098:Reproduction / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000502:physiology*
D019313:BRCA1 Protein; C000605931:Brca1 protein, mouse; D012333:RNA, Messenger; D018035:Receptors, Odorant; D025521:Tumor Suppressor Proteins