Mammary-derived signals activate programmed cell death during the first stage of mammary gland involution

Conversion of a solid primordium to a hollow tube of cells is a morphogenetic process used frequently during vertebrate embryogenesis. In the early mouse embryo, this process of cavitation transforms the solid embryonic ectoderm into a columnar epithelium surrounding a cavity. Using both established cell lines and normal embryos, we provide evidence that cavitation in the early mouse embryo is the result of the interplay of two signals, one from an outer layer of endoderm cells that acts over short distances to create a cavity by inducing apoptosis of the inner ectodermal cells, and the other a rescue signal mediated by contact with the basement membrane that is required for the survival of the columnar cells that line the cavity. This simple model provides a paradigm for investigating tube morphogenesis in diverse developmental settings.

Signal transduction pathways enable extracellular signals to activate latent transcription factors in the cytoplasm of cells. Dimerization, nuclear localization and binding to specific DNA sequences result in the induction of gene transcription by these proteins. These events are necessary for the functioning of the JAK/STAT pathway and of the glucocorticoid-receptor pathway. In the former, the protein Stat5, which is a member of a family of signal transducers and activators of transcription, is activated by cytokines, hormones and growth factors. These polypeptide ligands bind at the outside of the cell to specific transmembrane receptors and activate intracellular Janus protein tyrosine kinases (JAKs) to tyrosine-phosphorylate STAT proteins; interaction with the SH2 domain of the dimerization partner then confers the ability to bind to DNA at the STAT-response element and induce transcription. In the glucocorticoid-receptor pathway, the receptor interacts with its steroid hormone ligand in the cytoplasm, undergoes an allosteric change that enables the hormone receptor complex to bind to specific DNA-response elements (glucocorticoid response elements, or GRE) and modulate transcription. Although these pathways appear to be unrelated, we show here that the glucocorticoid receptor can act as a transcriptional co-activator for Stat5 and enhance Stat5-dependent transcription. Stat5 forms a complex with the glucocorticoid receptor which binds to DNA independently of the GRE. This complex formation between Stat5 and the glucocorticoid receptor diminishes the glucocorticoid response of a GRE-containing promoter.

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 h without milk in their stomachs. OT injection into the dams restores the milk injection in response to suckling. These results indicate an absolute requirement for oxytocin for successful milk injection, but not for mating, parturition and milk production, in mice.