Signal transducer and activator of transcription (Stat) 5 controls the proliferation and differentiation of mammary alveolar epithelium

Functional development of mammary epithelium during pregnancy depends on pr olactin signaling. However, the underlying molecular and cellular events ar e not fully understood. We examined the specific contributions of the prola ctin receptor (PrIR) and the signal transducers and activators of transcrip tion 5a and 5b (referred to as Stat5) in the formation and differentiation of mammary alveolar epithelium. PrIR- and Stat5-null mammary epithelia were transplanted into wild-type hosts, and pregnancy-mediated development was investigated at a histological and molecular level. Stat5-null mammary epit helium developed ducts but failed to form alveoli, and no milk protein gene expression was observed. In contrast, PrIR-null epithelium formed alveoli- like structures with small open lumina. Electron microscopy revealed undiff erentiated features of organelles and a perturbation of cell-cell contacts in PrIR- and Stat5-null epithelia. Expression of NKCC1, an Na-K-Cl cotransp orter characteristic for ductal epithelia, and ZO-1, a protein associated w ith tight junction, were maintained in the alveoli-like structures of PrIR- and Stat5-null epithelia. In contrast, the Na-Pi cotransporter Npt2b, and the gap junction component connexin 32, usually expressed in secretory epit helia, were undetectable in PrIR- and Stat5-null mice. These data demonstra te that signaling via the PrIR and Stat5 is critical for the proliferation and differentiation of mammary alveoli during pregnancy.