During this reporting period the Laboratory of Genetics and Physiology has made progress in the understanding of mechanisms that control the development and function of mammary tissue and pancreatic beta cells. We have discovered several years that the lactogenic hormone prolactin controls mammary development and differentiation during pregnancy through the transcription factor Stat5, and that interleukin 6 modulates the remodeling process of mammary tissue during the phase after weaning, called involution, through the transcription factor Stat3. However, it was not clear to what extent these two transcription factors are subject to positive or negative regulation. We have now discovered that a molecule called SOCS3 negatively regulates Stat3 but not Stat5. Mice from which the gene encoding SOCS3 has been deleted specifically from mammary stem / progenitor cells and mammary epithelium fail to undergo normal mammary tissue remodeling during the phase of involution. This is due to an aberrant activation of Stat3, which was caused by the loss of the negative regulator SOCS3. ? There had been an extended amount of literature reporting that cytokines control the proliferation, function and survival of pancreatic beta cells through the transcription factor Stat5. These findings were of potential importance since they could open the door to stimulate beta cell proliferation, survival and function in diabetic patients. However, these studies had been performed to a large extent in tissue culture cells and the relevance for in vivo settings was not known. To address this question we deleted the transcription factor Stat5 specifically from pancreatic cells of mice and explored the physiological consequences. We determined that cytokine signaling through Stat5 was dispensable for the development and differentiation of the different pancreatic lineages. However, the fitness of pancreatic beta cells during aging was impaired in the absence of Stat5. This suggests that cytokines modulate the physiology of pancreatic islets in situations of stress.
Showing the most recent 10 out of 113 publications
