Research Report 2010 - MDC

Daniel Besser(Delbrück Fellow)Structure of the GroupGroup LeaderDr. Daniel BesserGraduate StudentsSebastian DieckeAngel Quiroga-NegreiraTorben RedmerSignaling Mechanisms in EmbryonicStem CellsEmbryonic stem cells (ESC) are pluripotent cells, which can proliferate indefinitely andparticipate in the formation of most cell types. Studies on human ESCs (hESC) provide aninsight into human embryogenesis and allow the development of tools for pharmacology andregenerative medicine. The focus of our studies is the maintenance of the pluripotent state inmurine ESCs (mESCs) and hESCs. We found that the Activin/Nodal pathway is activated inpluripotent hESCs and blocked upon differentiation. Pluripotent cells require these signalingregulating a specific subset of target genes. In addition, the BMP pathway is in the off-state inpluripotent cells and activated upon differentiation. This pathway counteracts the effects ofActivin signaling. Moreover, it has been shown that somatic cells for various sources can bereprogrammed by transfection of four defined transcription factors, i.e. Oct4, Sox2, Klf4, andc-Myc, to a pluripotent state. These induced pluripotent stem cells (iPS) are very exciting newcell populations for stem cell research.Role of TGFβ signaling in pluripotency ofembryonic stem cellsAngel Quiroga-Negreira, funded by the DFG, SPP1109Embryonal and Tissue-specific Stem Cells and HGF-systemsbiology NW1 SB Cancer DKFZ.I.4Our previous observations show that Activin/Nodal signalingis required for maintenance of the undifferentiatedstate in hESCs while BMP signaling induces differentiation.This raises important questions regarding thedownstream target genes that are important for theregulation of pluripotency as well as differentiation.Another important question is how cross talk betweenthese two pathways is established. In this project wehave found that intrinsic Activin/Nodal and BMP signalingin hESCs controls the molecular events and theregulation of a whole set of downstream target genes.In a recent analysis of global expression profiles usingAffymetrix microarrays in a dense time course in hESCsand mESCs upon differentiation, activation and inhibitionof Activin/Nodal signaling and activation of BMPsignaling we gained deeper insight into the regulatoryevents underlying these processes. Moreover, by mathematicalmodeling we are in the process of using thisdataset for a detailed analysis of gene regulation inpluripotent ESCs and during early differentiation. Wefound that in hESCs, Activin A treatment under differentiatingconditions leads to establishment of thepluripotency program, while inhibition of Activin signalingand BMP4 treatment strongly induces differentiationinto specific cell lineages. The data also suggestthat molecules that regulate cell-cell interaction andcell motility, especially molecules of the Cadherin familyand molecules regulating the small GTP-binding proteinRho are regulated very early after induction of differentiation.Regulation of Oct4: How the regulator isregulatedSebastian Diecke and Angel Quiroga-NegreiraIt is well established that three transcription factors, i.e.Oct4 (Oct3/4, Pou5F1), Nanog, and Sox2 that interactwith each other, are at the core of the molecular events86 Cancer Research