Lothar Hennighausen (NIDDK)
Conditional knockout of Stat5a and Stat5b: Combined deletion of conserved Stat5a and Stat5b in mammary epithelium at different times during pregnancy reveal multiple distinct functions.
The signal transducer and activator of transcription (STAT) family of transcription factors conveys signals from membrane receptors to the nucleus, where they activate diverse genetic programs. Stat5a and Stat5b are highly conserved proteins that are activated by many cytokines, erythropoietin, prolactin and growth hormone. Despite their similarities, they have many unique functions. Stat5a deficiency results in the loss of prolactin-dependent mammary gland development, but does not affect body growth. Inactivation of Stat5b does not adversely affect mammary development and function, but leads to severe growth retardation. To study the effects of combined deficiency of Stat 5a and 5b before and during pregnancy, loxP was added to the ends of a DNA fragment that contains the two genes which are located within a stretch of 110 kb on chromosome 11 in a head to head orientation with no other genes between them. The loxP-flanked fragment was introduced into the genome using homologous recombination, and deleted using two transgenic lines expressing Cre in mammary epithelium at different times. Deletion of Stat 5 before pregnancy prevents epithelial proliferation. Ductal characteristics are retained but differentiation into secretory alveoli does not occur. When deletion of Stat5 occurs late in pregnancy after differentiation has started, differentiation is halted and premature death occurs.
Mouse model to study mammopoietic and lactogenic signaling.