Research Report 2010 - MDC

In the morula of the early mouse embryo the Spry4 protein is expressed uniformly in all blastomeres. Upon differentiation, both Spry4 and Nanogare limited to the inner cell mass of the blastocyst. Cdx2 is a marker of the extra-embryonic lineage, showing that cells of this lineage are devoidof Spry4 or Nanog.Proliferation and pluripotency in stem cellsChristna Chap and Gitta BlendingerThe ability to derive multiple differentiated lineages is ahallmark of embryonic stem cells (ES cells). Since ES-celltransplanted into nude mice develop primitive tumors,ES cells are viewed as an ideal in vitro model for earlymammalian development and tumorigenesis. UsingES-cells differentiation, we identified Sprouty4 (Spry4)as a novel player of the pluripotency network. Also, in EScells Spry4 acts as an inhibitor of the ERK pathway toregulate pluripotency. Using ChIP assays, we establishedthat Spry4 is transcriptionally repressed byNanog. This repression is essential, since over-expressionof Spry4 renders ES-cells insensitive to differentiation.Consistent with a role for Spry4 in pluripotency, wefind its expression restricted to the inner cell mass ofmouse embryos (see Figure). Our results show thatSpry4 tightly regulates several signal pathways tomaintain the pluripotent state of ES cells. In the future,we will characterize specific mutants of Spry4 that likelyinfer commitment to differentiation lineages. Sincewe believe, that Spry4 impinges upon more pathwaysthan it is currently recognized, we intend to establishnew Spry4 mouse models allowing us to dissect cooperatingsignaling events in cancer and stem cells.Determinants of cancer stem cells activityIn collaboration with Peter Wend and Walter BirchmeierRecent evidence suggests that organ as well as cancerstem cells share core transcriptional and signalingmodules. This points towards the fact that both celltypes share a common ancestor. To understand if this istrue, we deployed genetic mouse models and studiedWnt/β-catenin and Bmp signaling in salivary glandstem cells. Our results imply that both Bmp and properWnt/β-catenin signals are required to properly controlcell division, apoptosis and differentiation of salivarygland stem cells. Significantly, if mutations in bothpathways are joined, a tenfold increase of stem cells isobserved. These stem cells are activated upon regenerationand are highly tumorigenic. In the future, we willdissect the transcriptional profiles of these stem cellsto understand their specific contribution to tumorigenesis.Selected PublicationsLee, E.Y., Cam, H., Ziebold, U., Rayman, J.B., Lees, J.A., and Dynlacht, B.D.(2002). E2F4 Loss suppresses Tumorigenesis in RB Mutant Mice Through aNovel Mechanism. Cancer Cell 2, 463-472.Cloud, J.E., Rogers, C., Reza, T.L., Ziebold, U., Stone, J.R., Picard, M.H., Caron,A.M., Bronson, R.T., and Lees, JA. (2002). Mutant mouse models reveal therelative roles of E2F1 and E2F3 in vivo. Mol. Cell. Biol. 22, 2663-2672.Ziebold, U., Caron, A., Bronson, R., and Lees, J.A. (2003). E2F3-loss has opposingeffects on different pRb-deficient tumors, resulting in suppression ofpituitary tumors but metastasis of medullary thyroid carcinomas. Mol.Cell. Biol. 18, 6542-6552.Boden, C., and Ziebold, U. (2004). Cell division – an Overview, inEncyclopedic Reference of Genomics and Proteomics in MolecularMedicine K. Ruckpaul and D. Ganten, Eds. Springer Verlag, Heidelberg.Tapon, N. and Ziebold, U. (2008). Invasion and metastasis: stem cells,screens and survival. EMBO Rep. 9, 1078-1083.PatentsMIT Case No. 8756 “ANTIBODY TO P10”.Cancer Research 89