Sex, parturition and motherhood without oxytocin?

Our understanding of the functions of oxytocin in mammals has recently been challenged by findings in transgenic mice in which the oxytocin gene has been knocked out. Mammals generally have only two posterior pituitary nonapeptide genes, for oxytocin and vasopressin, while some marsupials do not express oxytocin but do express a closely related peptide, mesotocin, which acts at the oxytocin receptor (Acher et al. 1995). Birds have arginine vasotocin and mesotocin (Acher et al. 1995), while among other vertebrates a subclass of cartilaginous fishes evidently produces oxytocin (Michel et al. 1993). Mice homozygous for deletion of exon 1 of the oxytocin gene, containing the oxytocin nonapeptide sequence, were produced by homologous recombination in mouse embryonic stem cells. Offspring from matings of the heterozygotes were in the correct Mendelian frequency, indicating no lethal developmental defects in the homozygotes, which later showed normal sexual maturation, with both males and females showing sexual behaviour and normal fertility (Nishimori et al. 1996). Young and colleagues (1996) used gene targeting to generate a mouse with most of the first intron and the last two of the three exons of the oxytocin gene eliminated. The amount of oxytocin gene transcripts in the supraoptic and paraventricular nuclei of homozygotes was 1% of the wild-type level, with less than 0·4% of the wild-type content of oxytocin in the pituitary gland, and no oxytocin detectable in blood plasma by RIA. In both types of oxytocin gene disablement, the only evident defect was a complete failure of postpartum homozygotes to transfer milk to the suckling young, which consequently did not survive unless the mothers were treated with exogenous oxytocin. Thus parturition and maternal behaviour proceeded without oxytocin, although these processes were not studied in detail. These findings are surprising in view of the vast literature on a wide range of species suggesting important roles for oxytocin in regulating gonadal function, in expression of sexual behaviour, in parturition and initiation of maternal behaviour as well as in lactation. It is appropriate to consider whether the results from the oxytocin knockout mice arise from peculiarities in the roles of oxytocin in the mouse in comparison with other species, or indicate redundancy in the mechanisms in which oxytocin normally has an important role; apart that is, from the milk-ejection reflex in which there is no evident redundancy, at least in the mouse.