Insights Into Parturition Biology From Genetically Altered Mice

Abstract

ABSTRACT:With the growing frequency of preterm birth, increased effort has been made to elucidate the physiology of normal and aberrant parturition. As with many developmental processes, the study of genetically altered mice has led to an increased understanding of mechanisms controlling the maintenance and resolution of pregnancy. Studies in genetically altered mice have implicated critical roles for both prostaglandin synthesis and degradation in luteolysis and the progression of labor. The importance of local modulation of progesterone activity to cervical ripening has also been demonstrated. Although a decline in levels of serum progesterone is a part of normal labor initiation in mice but not humans, murine labor without progesterone withdrawal has been reported in some cases. These findings emphasize the importance of other components of the parturition cascade that are shared in mice and humans and highlights the importance of an increased understanding of the physiology of mouse parturition. (Pediatr Res 64: 581-589, 2008) P arturition is the culmination of mammalian reproduction, a task essential for survival of the species. After a period of uterine quiescence to allow fetal growth and development, changes occur in myometrial contractility that result in efficient expulsion of the fetus. These events have likely evolved to enhance survival of both the fetus and the mother. The nature of these pathways, however, is at best incompletely defined.Increased knowledge of the cascade of events that occur at parturition may lead to advances in combating preterm labor (PTL) or optimization of protocols for medically induced labor. As preterm birth is associated with both increased risk of neonatal mortality and chronic sequelae such as respiratory illness, cerebral palsy, and vision and hearing impairment, it is a major public health concern (1). In the United States, 12.7% of births are preterm (2). Although approximately 50% of preterm births are idiopathic (3), genetic factors seem to be important. Women whose mothers or sisters delivered preterm are at increased risk for premature labor (4,5), indicating a genetic component in the timing of labor. In addition, a study of a Utah population indicates greater genetic relatedness between families with preterm deliveries than control families (6). Because the population studied was descended from the people who established Mormonism in Utah and Mormons have low rates of substance abuse and sexually transmitted diseases, the population used in this study may represent individuals with few environmental risk factors for PTL (6). These studies highlight a role for genetic, and not just environmental factors in predisposition to PTL and serves as a call to researchers to identify and study genes important for parturition.The mouse is a useful research tool for dissecting genetic factors involved in developmental processes. Mice are tractable to genetic manipulation, resulting in an array of available and potential knockout and transgenic mice suitable for studying t...

Uterine-specific p53 deficiency confers premature uterine senescence and promotes preterm birth in mice

“…It is known that liver- and lung-type PGFSs are highly expressed in the mouse uterus just prior to parturition (42). PGF 2α is known to play an important role in the initiation of parturition in mice (43). Studies in mice with deletion of PGF receptor FP (Ptgfr -/-) show that PGF 2α acts on ovarian FP receptors to induce luteolysis, leading to the fall in P 4 levels required for triggering labor (44).…”

Determinants of uterine aging: lessons from rodent models

“…Parturition is the culmination of mammalian reproduction, which is a task essential for survival of the species and facilitated by the myometrial contractility. During the pregnancy, the uterine quiescence is maintained through a sustained high level of progesterone [30]. Prior to the labor, a decrease in progesterone levels or functional progesterone withdrawal synergizes with other contractile mediators to disrupt the myometrial relaxation resulting in efficient expulsion of the fetus [31].…”

Preventing preterm birth: the past limitations and new potential of animal models

“…1), the genetic tractability of the mouse makes it an attractive mammalian model system (Ratajczak and Muglia, 2008). This allows for the generation of knockout models to examine the role of genes that might influence parturition.…”

“…1). Furthermore, whereas humans experience a luteal-placental shift, the mouse corpora lutea are responsible for steroid hormone production throughout gestation (for a review, see Ratajczak and Muglia, 2008).…”

“…1). Furthermore, whereas humans experience a luteal-placental shift, the mouse corpora lutea are responsible for steroid hormone production throughout gestation (for a review, see Ratajczak and Muglia, 2008).As with sheep, mouse parturition involves progesterone withdrawal. Whereas in the sheep, the placenta has a role in steroid hormone production during pregnancy, the corpora lutea of the mouse ovaries are responsible for steroid production throughout pregnancy.…”