Generation and phenotypic analysis of coronin-1 deficient mice

Coronins represent an evolutionary conserved family of WD-repeat actin-binding proteins for which a role in regulating membrane and cytoskeleton related functions have been proposed. In mammalian organisms seven members of the coronin protein family have been described of which coronin-1 respresents the thus far best characterized molecule. Coronin-1 is specifically expressed in leukocytes and was originally identified as a key player in mediating the survival of pathogenic mycobacteria in infected murine macrophages by inhibiting the fusion of the mycobacterial phagosome with lysosomes. Further analyses demonstrated the capacity of coronin-1 to link the leukocyte plasma membrane with the underlying actin cytoskeleton suggesting a regulatory role of coronin-1 in leukocyte specific functions. However, a precise biological activity of coronin-1 in leukocytes and in mammalian organisms in general has not yet been defined. The aim of the work described in this thesis was to contribute to our understanding of the function of coronin-1 by generating and phenotypically characterizing coronin-1 knock-out mice. Coronin-1 deficient mice were found to be viable and fertile. In-depth analysis of the immune system revealed that the lack of coronin-1 expression severly affected the homeostasis of the peripheral T-cell pool. Whereas T-cell development could be shown to be independent on coronin-1, peripheral T-cell numbers were found to be strongly reduced. The reduction of peripheral T-cell numbers in coronin-1 deficient mice was accompanied by changes in the composition and function of the peripheral T-cell pool. Coronin-1 deficient peripheral T-cells were prone to apoptosis, less efficient in homing to secondary lymphoid organs and unable to mount a proliferative response to allogeneic MHC stimuli. Cytoskeletal structures in coronin-1 deficient T-cells were found to be normally organized. Coronin-1 deficiency did not affect other leukocyte subsets, such as B-cells and macrophages. Macrophages isolated from coronin-1 deficient mice did neiter show any abnormalities in the organization of the actin cytoskeleton nor did the absence of coronin-1 expression affect their phagocytic properties. We therefore conclude that coronin-1 plays a crucial role in maintaining T-cell but not macrophage functions. Based on the results described in this thesis we propose a function of coronin-1 in regulating T-cell homeostasis by modulating T-cell specific functions such as T-cell activation.