Note: mini-review on oxytocin
Summary Oxytocin is a nonapeptide hormone that participates in the regulation of parturition and lactation. It has also been implicated in various behaviors, such as mating and maternal, and memory. To investigate whether or not oxytocin (OT) is essential for any of these functions, we eliminated, by homologous recombination, most of the first intron and the last two exons of the OT gene in mice. Those exons encode the neurophysin portion of the oxytocin preprohormone which is hypothesized to help in the packaging and transport of OT. The homozygous mutant mice have no detectable neurophysin or processed oxytocin in the paraventricular nucleus, supraoptic nucleus or posterior pituitary. Interestingly, homozygous mutant males and females are fertile and the homozygous mutant females are able to deliver their litters. However, the pups do not successfully suckle and die within 24 hours without milk in their stomachs. OT injection into the dams restores the milk ejection in response to suckling. These results indicate an absolute requirement for oxytocin for successful milk ejection, but not for mating, parturition and milk production, in mice.
OT is also required for post-partum alveolar proliferation and mammary gland development. Alveolar density and mammary epithelial cell differentiation at parturition was similar in wildtype and OT-deficient dams. While approximately 2% of the alveolar cells in wildtype dams incorporated DNA and proliferated within 12 hours after parturition, almost no proliferation was detected in OT-deficient dams. Continuous suckling of pups led to the expansion of lobulo-alveolar units in wildtype but not in OT-deficient dams. Despite suckling and the presence of systemic lactogenic hormones, mammary tissue in OT-deficient dams partially involuted. Our studies demonstrate that post-partum alveolar proliferation requires not only systemic lactogenic hormones, such as prolactin, but also the presence of OT in conjunction with continued milk removal.
Introduction Hormones of the pituitary gland regulate mammogenesis and lactation. Prolactin (PRL) is synthesized in the anterior pituitary gland and is required for the proliferation and maintenance of lobulo-alveolar structures. Oxytocin (OT) is released from the posterior pituitary gland upon a suckling stimulus by the young. It induces contraction of myoepithelial cells surrounding the alveoli causing ejection of milk. OT is a nonapeptide whose sequence was identified by Du Vigneaud and colleagues. OT is synthesized as an oxytocin-neurophysin preprohormone in specialized magnocellular neurons of the paraventricular and supraoptic nuclei of the hypothalamus. After cleavage of the signal peptide, OT is processed during transport within secretory granules in magnocellular neurons to the posterior pituitary gland where it is secreted into the circulation. Some OT synthesis has been found in the uterus, placenta, corpus luteum, testes and the amnion of various species.
The ancestral gene for the oxytocin/vasopressin superfamily was already present in the Archaemetazoa about 600 million years ago. The conservation of this gene in vertebrates and invertebrates suggests that OT has important functions that are not restricted to its "galactogogic effect" in mammals. OT has a uterotonic effect and plays an important role during the initiation and maintenance of parturition. Furthermore, OT has been postulated to be required for memory, mating behavior, natri- and antidiuresis, fertility, and maternal behavior in rodents. However, recent studies in mice in which both alleles of the oxytocin gene had been inactivated demonstrated that OT is essential only for lactation and milk ejection.
The concept of the neuroendocrine milk ejection reflex was first described by Ely and Pedersen. Nipple stimulation leads to the release of OT from the posterior pituitary into the blood stream, and subsequently to milk ejection as a result of the contraction of the mammary myoepithelium. Mice deficient in OT are unable to nurse the litter, but exogenous administration of OT restored myoepithelial contraction and dams were able to feed their young. There is some indication that OT also contributes to the development of the mammary gland. From in vitro and in vivo studies, Sapino and coworkers suggested that OT directly induces myoepthelial cell growth and differentiation by enhancing the effect of lactogenic hormones. Further support for a proliferative role of OT comes from in vitro studies of neuronal tissues. For example, the rate of proliferation in rat cortical and hypothalamic astroglia cells increased after OT administration in vitro. However, OT may also have an inhibitory effect in some human breast cancer cell lines. As a releasing factor for PRL, OT could also act indirectly on mammary gland development. The OT receptor (OT-R) is expressed in the lactrotrophs of the pituitary gland and OT might control PRL release. As a lactogenic hormone, PRL is a principal mediator of mammogenesis. Recent studies have shown that the disruption of the PRL signaling pathway leads to an impaired development of lobulo-alveolar structures.
Initial analysis of OT-deficient dams revealed sparse mammary alveolar development. Here we test the hypothesis that OT controls, directly or indirectly, development of the mammary gland. In particular, we examined lobulo-alveolar proliferation and outgrowth in post-partum dams. Our findings suggest that the impaired milk release caused by the absence of OT inhibits a further outgrowth of the lobulo-alveolar structures and initiates the programmed cell death even in the presence of lactogenic hormones which are released during suckling. However, OT is not required for the terminal differentiation of myoepithelial cells and has no significant effect on the release of lactogenic hormones from the anterior pituitary. Mice deficient in OT therefore served as an excellent model to segregate the effects of systemic vs. local factors for maintenance and programmed cell death of lobulo-alveolar structures in the mammary gland.
Citation W. Scott Young, III, Emily Shepard, Janet Amico&dagger, Lothar Hennighausen, Kay-Uwe Wagner, Mary E. LaMarca, Cindy McKinney and Edward I. Ginns (1996) J. Neuroendocrinol. 8: 847-853.
Kay-Uwe Wagner, W. Scott Young III, Xiuwen Liu, Edward I. Ginns, Minglin Li, Priscilla A. Furth and Lothar Hennighausen (1997) Oxytocin and milk removal are required for post-partum mammary gland development. Genes and Function, in Press.
Keywords oxytocin
Contributed by
Kay-Uwe Wagner
National Institutes of Health
Bethesda, MD 20815
tel. 301-496-8727
FAX 301-496-0839
Scott Young
National Institutes of Health
Bethesda, MD 20892
Phone: (301) 496-8767
Fax:
e-mail: scott@zippy.nimh.nih.gov
established: January 1997
last update: June, 1998