What knockout mice can tell us about parturition

Abstract

Many molecules, including steroid and peptide hormones, prostaglandins and cytokines, regulate the preparation, initiation and progression of parturition in mammals. Gene targeting studies show that, in the knockout mice of steroid 5α-reductase type 1 gene, prostaglandin F 2α receptor gene and cytosolic phospholipase A 2 gene, parturition was severely disturbed, although live offspring were delivered by Caesarean section. Relaxin gene-disrupted mice also showed protracted labour. However, most knockout mice in which the steroid hormone, prostaglandin, cytokine or peptide hormone (for example, oxytocin, corticotrophin releasing hormone and endothelin) endocrine-paracrine systems are disrupted are inadequate for analysis of the mechanism of parturition because they die before reaching reproductive age or are infertile, or because they reproduce normally. A conditional knockout strategy, for example, using the Cre-LoxP system, should be considered for investigating the biochemical background of parturition to overcome these problems.hormones produced by the fetus can cross the placenta to some extent and may affect maternal (GR +/-) uterine function, although the maternal GR is partially ablated. However, it would appear that disturbed fetal corticosterone metabolism does not affect parturition in mice.Near to term of human pregnancy, there is a 100-fold higher concentration of circulating oestrogens, produced mainly from placental tissue, than in non-pregnant women in whom the oestrogens derive predominantly from the ovary. As the oestrogen concentrations increase gradually towards the onset of parturition, maternal oestrogen is important for uterine preparedness. Oestrogen receptor knockout mice (ERα -/-) are externally normal in both sexes. Internally, only ERα -/-females showed noticeable gross differences from normal females. ERα -/-females are completely infertile, with hypoplastic uteri and hyperemic ovaries (Lubahn et al., 1993), so that any effect on parturition cannot be studied. Details of oestrogen receptor β(ERβ)-knockout mice have not yet been published. Oestrogens are the final products of the steroidogenesis pathway. Therefore, the disruption of aromatase cytochrome P450, that is, the cyp19 gene product, could impair the biosynthesis of oestrogens without disturbing the biosynthesis of other steroid hormones. Aromatase knockout mice have been reported; again aromatase -/-(ArKO) homozygous females were completely infertile (Fisher et al., 1998). Adult male and female ArKO mice exhibit higher concentrations of testosterone and androstenedione, the precursors of oestrogens; however, the authors did not investigate fetal or neonatal androgen concentrations. It is not known whether an oestrogen supplement given to ArKO mice from the neonatal period might recover female fertility. If it is possible for female ArKO mice to become pregnant, the role of oestrogen during pregnancy could be analysed by studying the effects of stopping oestrogen supplementation at different stages of pregnancy. Natural aromatas...

Differential impact of prostaglandin H synthase 1 knockdown on platelets and parturition

“…During parturition, labor can be separated into 2 phases after uterine quiescence (43). Progesterone plays an essential role in the preparation for and maintenance of pregnancy and is elevated during quiescence.…”

“…Surprisingly, OTR expression appears to be even greater in the hypomorphic PGHS1 Neo/Neo female mice (in which PGF 2α levels are lower but OTR levels are higher) at late gestation, perhaps as a compensatory mechanism in vivo whereby the signaling components are reprogrammed to new set points vis-à-vis WT controls to coordinate uterine contraction at term. PGF 2α derived from PGHS1 induction in the ovary (10) triggers onset of labor, which is essential for luteolysis and the decline in serum progesterone (8,43). Thus, minimal PGHS1 expression is sufficient for these physiological procedures to initiate term parturition.…”

Overview of Current Research in Parturition

“…Several other murine knockout phenotypes have been generated and have been reviewed recently (Kimura et al 1999;Gross et al 2000a). Bond et al (2000) have described a mouse phenotype where conditional overexpression of the voltage-independent potassium channel subunit SK3 results in abnormal parturition due to exaggerated hyperpolarization of uterine smooth muscle cells and severely protracted delivery.…”

Cervical maturation and labor induction

“…13) In the relaxin gene knockout mice, prolonged labor can be observed, in relation with absent cervical ripening. 14) Contrary to other cervical ripening hormones, relaxin does not induce uterine contractions but has a relaxing effect on the myometrium. 3,15) It is thus believed to play a role in the conditioning phase of the cervix, far ahead of labor.…”