For their well being hematopoietic stem cells (HSC) need a cocktail of cytokines. As a common theme, these cytokines activate the transcription factors Stat3 and Stat5a and Stat5b (STAT5), which supposedly control some aspects of stem cell biology. Notably, the forced expression of retrovirally-encoded constitutively active STAT5a in HSCs can enhance their viability. Having said this, these experiments are based on the forced expression of STAT5 and the true in vivo function of STAT5 in the life of a HSC is not known. Scientist in the Laboratory of Genetics and Physiology (LGP) now explore the function of cytokines signaling through STAT5 in stem cell biology using genuine and cell-specific STAT5-ko mice.
Investigators: BingMei Zhu, Risu Na, Akiko Kimura.
Collaborators: Michael Rieger and Timm Schroeder.
Cytokine signaling in mammary gland development and cancer
Cytokines and their down stream transcription factors STATs control many aspects of mammary gland biology. We have shown that prolactin signaling through STAT5 is required for development, maintenance and differentiation of secretory epithelial cells. STAT3 activated by IL-6 regulates the apoptotic process in post lactational weaning. STAT1 is thought to be involved in immune surveillance and carcinogenesis. In LGP we generated mice with conditional alleles of Stat1 and Stat5, which allow us to delete these genes at different developmental stages. We are also in the process of generating inducible alleles of Stat5 that will allow us to regulate the timing of STAT5 expression. Our current research is focused on identifying the genes that mediate the action of cytokine signals in mammary epithelium.
Investigators: Gertraud Robinson, Peter Klover, Risu Na, Daisuke Yamaji
Epo/STAT5 signaling in erythropoiesis
Mice that lack the STAT5 locus exhibit severe anemia and die perinataly. Current research focuses on the role of STAT5 in the proliferation and differentiation of erythroid cells.
Investigators: BingMei Zhu
Collaborators: Sara Koenig and Nancy Andrews
The role of cytokines and STATs in cancer
Aberrant cytokine signaling, which results in the activation of STAT5, has been attributed to many hematopietic disorders, including AML, CML and Polycythemia Vera as well as solid tumors. We use conditional STAT5 ko mice to investigate the importance of STAT5 in the initiation and progression of leukemias and breast cancer. Part of this program is built on mice generated in LGP in which the entire STAT5a/b locus has been bracketed by loxP sites and thus can be deleted in a cell-specific and temporal fashion.
Investigators: BingMei Zhu, Risu Na, Peter Klover and Daisuke Yamaji.
Collaborators: Gerlinde Wernig, Gary Gilliland, William Muller.
Cytokine signaling in metabolism
Cytokines, such as leptin and CNTF, control satiety and metabolism by signaling through specific hypothalamic neurons. Dr. Ji-Yeon Lee has discovered that mice, which have lost STAT5 in the CNS develop severe late onset obesity. Current studies focus on the identification of the cytokine that activates STAT5 in the CNS, the responsible neurons and the underlying mechanisms.
Investigators : Ji-Yeon Lee.
Collaborators : Oksana Gavrilova, Heike Muenzberg and Martin Myers.
Cytokine signaling in muscle biology and diabetes
Investigator : Peter Klover
Cytokine signaling in liver disease
Investigator : Atsushi Hosui