Transgene insertion on mouse chromosome 6 impairs function of the uterine cervix and causes failure of parturition.
The molecular mechanisms controlling the initiation of parturition remain largely undefined. We report a new animal model in which parturition does not occur. A line of mice expressing a human apolipoprotein B (APOB) gene fail to deliver their young if the transgene is present in homozygous (Tg/Tg), but not in heterozygous (Tg/Wt), form. Cloning and mapping of the transgene insertion locus indicate that 10 copies of the 80-kilobase APOB genomic fragment inserted into mouse chromosome 6 result in a small, 390-base pair deletion of mouse genomic DNA. Nine other lines expressing the transgene have normal labor, suggesting that transgene insertion in this mutant line disrupted a mouse gene crucial for successful parturition. The pathophysiology of parturition failure in these animals was defined using physiological, endocrinological, and morphological techniques. Results indicate that luteolysis occurs in Tg/Tg mice but is delayed by 1 day. Delivery did not occur in mutant mice at term after spontaneous luteolysis or even after removal of progesterone action by ovariectomy or antiprogestin treatment. Biomechanical and functional studies of the uterus and cervix revealed that the primary cause of failed parturition in Tg/Tg mice was not inadequate uterine contractions of labor but, rather, a rigid, inelastic cervix at term that was abnormally rich in neutrophils and tissue monocytes. Characterization of the transgene insertional mutant, Tg/Tg, indicates that progesterone withdrawal is insufficient to complete parturition in the presence of inadequate cervical ripening at term.
Word
R Ann
RA
Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas 75390, USA.
Landrum
Charles P
CP
Timmons
Brenda C
BC
Young
Stephen G
SG
Mahendroo
Mala S
MS
D004092:20-alpha-Dihydroprogesterone / Q000378:metabolism; D000818:Animals; D002584:Cervix Uteri / Q000378:metabolism / Q000503:physiopathology*; D002875:Chromosomes; D005260:Female; D020869:Gene Expression Profiling; D006720:Homozygote; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics*; D010121:Oxytocin / Q000378:metabolism; D036801:Parturition / Q000235:genetics* / Q000502:physiology; D011247:Pregnancy; D011374:Progesterone / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D014590:Uterine Contraction / Q000235:genetics
D004092:20-alpha-Dihydroprogesterone; D011374:Progesterone; D010121:Oxytocin