Expression by Transgenesis of a Constitutively Active Mutant Form of the Prolactin Receptor Induces Premature Abnormal Development of the Mouse Mammary

Prolactin (PRL) initiates signal transduction by inducing hom-odimerization of PRL receptor (PRL-R). We have previously de-veloped a mutant form of the PRL-R in which a part of the ex-tracellular domain is deleted. This receptor constitutively acti-vates protein gene transcription. We examined the oligomeri-zation of the mutant PRL-R using two differently epitope-tagged receptors in a coimmunoprecipitation assay. It was shown that mutant receptor dimers were formed in a ligand-independent manner, which may explain the constitutive activity on milk pro-tein gene expression. To study the biological activity of this mu-tant PRL-R on mammary gland development, we generated two lines of transgenic mice expressing the corresponding cDNA specifically in the mammary epithelial cells. For both transgenic lines, the mammary gland of 8-wk-old virgin mice was overde-veloped with numerous dilated ductal and alveolar structures, whereas only a limited duct network was present in wild-type animals at the same age. During pregnancy, the ducts and alveoli of transgenic mice were more developed than those of control animals. At parturition, the transgenic animals failed to lactate and nourish their offspring, and the involution of the mammary gland was strongly delayed. In conclusion, the expression of a constitutively active PRL-R by transgenesis induces a premature and abnormal mammary development and impairs terminal dif-ferentiation and milk production at the end of pregnancy. cytokines, early development, mammary glands, mechanisms of hormone action, prolactin recepto