Characterisation of microglia specific Tgfbr2 Smad4 and Tgfb1 knockout mice Zusammenfassung: This thesis was conducted to describe the role of TGFβ mediated regulation of microglia homeostasis and activation. To this aim I generated and characterised microglia specific knockout mouse lines to analyse the importance of R SMAD dependent (mgTgfbr2 ) and Co SMAD dependent (mgSmad4 ) TGFβ signalling in microglia. Moreover microglia specific deletion of Tgfb1 (mgTgfb1 ) was induced to address the effects of microglia derived TGFβ1. According to the current literature this is the first study using mouse lines with microglia specific knockout of TGFβ signalling molecules.I could show that the generated mouse lines are valid models for the microglia specific analysis of TGFβ signalling as demonstrated by deletion on genomic and protein levels. Importantly functional impairment of TGFβ signalling could be detected in vitro and in vivo. The knockout mice were used to reveal that microglial TGFβ signalling is not essential for microglia survival and maintenance as no differences were seen in microglia cell numbers in vivo. Elevated cell numbers in vitro indicated an increased proliferative activity of mgTgfbr2 microglia. Furthermore mice did not show any phenotypic differences with regard to body weight or survival. Additionally using mgSmad4 mice I could show that the expression of distinct TGFβ induced genes was dependent on SMAD4. Interestingly TGFβ driven nuclear translocation of R SMADs in microglia was independent on SMAD4.I could show that knockout of microglial Tgfbr2 but not of Smad4 or Tgfb1 led to an activated microglia phenotype under physiological conditions as reflected by increased expression activation markers CD86 CD206 CD36 and MHCII. mgTgfbr2 microglia also showed an increase of TAK1 phosphorylation as well as CCL2 and CXCL10 secretion. In contrast knockout of Smad4 only led to a moderate increase of TAK1 phosphorylation and secretion of CCL3 and CCL4 in vitro. I could therefore show that the effects mgTgfbr2 and mgSmad4 knockout resulted in different outcome indicating a major role of R SMAD dependent signalling in the regulation of microglia activation under physiological conditions. However distinct and partially non overlapping effects were detected in mgSmad4 microglia indicating a contribution of Co SMAD dependent signalling for microglia quiescence. Exogenous TGFβ1 was no longer able to attenuate IFNγ induced upregulation of the activation markers iNos and Tnfa in Tgfbr2 ...