A plethora of cytokines signal through the Jak2/Stat5 pathway and thereby control a cell's response to its environment. Our laboratory employs a "system biology" approach using experimental mouse and zebrafish genetics to understand the contribution of this signaling cascade in the framework of different cell types and different physiological settings. Specifically, we focus on Jak2/Stat5 signaling in the mammary gland, pancreas, liver, and muscle. In the mammary gland, the Jak2/Stat5 pathway is essential for the specification, proliferation, differentiation and possibly survival of secretory epithelium (1-4). Although the signal transducers and activators of transcription Stat5a and Stat5b are highly conserved (5) they play distinct roles in the physiology of the cell. Notably, only Stat5a and not Stat5b is required for the differentiation of mammary epithelium (2, 6). While Stat5a is not necessary for the proliferation of mammary epithelium per se, no secretory alveolar epithelium is formed in the combined absence of Stat5a and Stat5b (3).
Inactivation of the Stat5a/b locus in the mouse germline results in an altered physiology of several distinct cell types, including the henmatopoietic system. However, to fully understand the contributions of the Jak2/Stat5 signaling pathway in distinct cell types and different stages of development and physiology, it is necessary to conditionally inactivate these genes. Towards this end we have cloned and characterized the locus that contains the genes encoding Stat5a, Stat5b and Stat3 (7, 8).
Based on this information we have generated targeting vectors and bracketed the Stat5a and 5b genes with loxP sites (Figure 1). ES cells as well as mice were generated that carry the targeted Stat5 locus. These mice are being used for two sets of experiments. First, with the help of transgenic mice expressing Cre in the female germline, mice were generated that carry one true Stat5-null allele and one wild-type allele. These mice are being crossed to explore the consequences of mouse development and physiology in the complete absence of Stat5. Secondly, the cell-specific contributions of Stat5-mediated cytokine signaling will be explored upon deletion of the Stat5 locus in specific cell types in vivo using Cre expressing transgeneic mice, and in primary cells. The cell types under investigation include, mammary cells, hepatocytes, the hematopoietic lineage and pancreatic beta cells.
Current investigators: Karen Cui, Sanita Bharti, Ji-Yeon Lee, Traudl Robinson
Past LGP investigators: Xiuwen Liu, Keiko Miyoshi, Kay-Uwe Wagner, Greg Riedlinger, Brian Bierie, Wei Tang
Collaborators: Chu-Xia Deng
Past Collaborators: Bernd Groner, Tony Wynshaw-Boris, Lisa Garrett
Relevant references
1. Hennighausen, L. and Robinson, G.W. (2001) Signaling pathways in the mammary gland. Developmental Cell, 1, 467-475.
2. Liu, X., Robinson, G.W., Wagner, K.-U., Garrett, L., Wynshaw-Boris, A. and Hennighausen, L. (1997) Stat5a is mandatory for adult mammary gland development and lactogenesis. Genes and Dev. 11, 179-186.
3. Miyoshi, K., Shillingford, J.M., Smith, G.H., Grimm, S.L., Wagner, K.U., Oka, T., Rosen, J.M., Robinson, G.W. and Hennighausen, L. (2001) Signal transducer and activator of transcription 5 (Stat5) controls the specification and proliferation of mammary alveolar epithelium. J. Cell Biol., 155, 531-542.
4. Shillingford, J.M., Miyoshi, K., Robinson, G.W., Grimm, S.L., Rosen, J.M., Neubauer, H., Pfeffer, K. and Hennighausen, L. (2002) Jak2 is an essential tyrosine kinase involved in pregnancy-mediated development of mammary secretory epithelium. Mol. Endo., in press.
5. Liu, X.-W., Goulliaux, F., Robinson, G.W., Groner, B. and Hennighausen, L. (1995) Identification and characterization of STAT5 and a novel homologue (STAT5b) involved in prolactin mediated signal transduction in mouse mammary tissue. Proc. Natl. Acad. Sci.U.S.A. 92, 8831-8835.
6. Teglund, S., McKay, C., Schuetz, E., Van Deursen, J.M., Stravapodis, D., Wang, D., Brown, M., Bodner, S., Grosveld, G and Ihle, J.N. (1998) Stat5a and Stat5b proteins have essential and nonessential, or redundant, roles in cytokine responses. Cell 93, 841-850.
7. Miyoshi, K., Cui, Y.K., Riedlinger, G., Robinson, P., Lehoczky, J., Zon, L., Oka, T., Dewar, K. and Hennighausen, L. (2001) Structures of the mouse and zebrafish Stat3/5 loci: Evolution from Drosophila to zebrafish to mouse. Genomics, 71, 150-155.
8. Cui, Y, Li, M., Walton, K.D., Sun, K., Hanover, J.A., Furth, P.A. and Hennighausen, L. (2001) The Stat3/5 locus encodes novel endoplasmic reticulum and helicase-like proteins that are preferentially expressed in normal and neoplastic mammary tissue. Genomics, 78, 129-134.
9. Wagner, K.-U., Wall, R.J., St-Onge, L., Gruss, P., Garrett, L., Wynshaw-Boris, A., Li, M., Furth, P.A. and Hennighausen, L. (1997) Cre mediated gene deletion in the mammary gland. Nucleic Acids. Res. 25, 4323-4330.
10. Wagner, K.U., McAllister, K., Ward, T., Davis, B., Wiseman, R. and Hennighausen, L. (2001) Spatial and temporal expression of the Cre gene under the control of the MMTV-LTR in different lines of transgenic mice. Transgenic Research, 10, 545-553.
11. Furth, P.A., St. Onge, L., Boger, H., Gruss, P., Gossen, M., Kistner, A., Bujard, H. and Hennighausen, L. (1994) Temporal control of gene expression in transgenic mice by a tetracycline responsive promoter. Proc. Natl. Acad. Sci. U.S.A. 91, 9302-9306.
Current investigators: Ji-Yeon Lee, Krista Buono, Traudl Robinson
Past LGP investigators: Brian Bierie
Collaborators: Laure Bally-Cuif Lab
website, Laboratory of Phil Ingham
Past Collaborators:
Relevant references
1. Miyoshi, K., Cui, Y.K., Riedlinger, G., Robinson, P., Lehoczky, J., Zon, L., Oka, T., Dewar, K. and Hennighausen, L. (2001) Structures of the mouse and zebrafish Stat3/5 loci: Evolution from Drosophila to zebrafish to mouse. Genomics, 71, 150-155.
Current investigators:Traudl Robinson
Past Investigators:
Collaborators: Esta Sterneck
Past Collaborators:
References
1. Robinson, G.W. Johnson, P.F., Hennighausen, L. and Sterneck, E. (1998) The C/EBPb transcription factor regulates epithelila cell proliferation and differentitaion in the mammary gland. Genes and Development, 12, 1907-1916.