Nesprins, nuclear dystrophin-like integrators of the cyto- and nucleoskeleton
Final Report Abstract
Nuclei are round structures within cells that house the genome. Nuclei are protected by a structural porous shell called the nuclear envelope. A novel group of massive molecules has been found by our laboratory that encapsulates the exterior of the nuclear envelope called the nesprins (nuclear envelope spectrin repeat proteins). While we knew that nesprins are important molecules in humans based on their role to cause fatal degenerative diseases, we lacked detailed information about their functions. Therefore, the aim of the proposal was to study novel nesprin interactions with the internal skeleton of cells, known as the cytoskeleton. Overall our data challenge previous concepts that the nuclear envelope is simply a barrier that isolates nuclei from the rest of the cell. Specifically, our results demonstrated that nesprins define the cytoskeleton architecture on the outside of the nuclear envelope and that they are part of a functional bridge that connects the interior of the nucleus with its outside environment. Moreover, our studies also revealed that the nesprins together with the cytoskeleton control the shape of nuclei, overall cell structure and behaviour. Specifically, we found that nesprins regulate the speed by which cells move, their directionality (known as polarity) and also the way by which they glue themselves to their environmen. Notably and quiet surprisingly, however, these molecules also control the communication within and between cells. In summary, our study shows that nesprins are important and multifunctional molecules of the nuclear envelope controlling fundamental aspects of cellular behaviour and architecture, which may explain why these molecules are involved in detrimental diseases such as muscle weakness (various types of muscular dystrophy), paralysis (ataxia), premature ageing (progeria) and cancer.
Publications
- KASH-domain proteins and the cytoskeletal landscapes of the nuclear envelope. Biochem. Soc. Trans. 36, 1368-1372. (2008)
Schneider M., Noegel A.A., and Karakesisoglou I.
- Nesprin-2 Giant/NUANCE maintains nuclear envelope architecture and composition in skin. J. Cell Sci. 121, 1887-1898. (2008)
Lüke Y., Zaim H., Karakesisoglou I., Jaeger V.M., Sellin L., Lu W., Schneider M., Neumann S., Beijer A., Munck M., Padmakumar V.C., Gloy J., Walz G., and Noegel A.A.
- Sun-proteins form immobile macromolecular assemblies at the nuclear envelope. Biochim. Biophys. Acta Mol. Cell Res. 1783, 2415-2426. (2008)
Lu W., Gotzmann J., Sironi L., Jaeger V.M., Schneider M., Lüke Y., Uhlén M., Szigyarto C.A., Brachner A., Ellenberg J., Foisner R., Noegel A.A., and Karakesisoglou I.
- Nesprin-2 interacts with -Catenin and regulates Wnt-signalling at the nuclear envelope. J. Biol. Chem. 285, 34932-34938. (2010)
Neumann S., Schneider M., Lu W., Eming S., Beijer A., Daugherty R.L., Noegel A.A., and Karakesisoglou I.
- Molecular mechanisms of centrosome and cytoskeleton anchorage at the nuclear envelope. Cell. Mol. Life Sci. 68, 1593-1610. (2011)
Schneider M., Lu W., Neumann S., Brachner A., Gotzmann J., Noegel A.A., and Karakesisoglou I.
- Nesprin interchain associations control nuclear size. Cell. Mol. Life Sci. [Epub ahead of print] (2012)
Lu W., Schneider M., Neumann S., Jaeger V., Taranum S., Richardson C., Goldberg M., Noegel A., and Karakesisoglou I.
(See online at https://doi.org/10.1007/s00018-012-1034-1) - Roles for nuclear envelope associated Nesprin-2 Giant in cell differentiation, proliferation and chromatin association in a mouse model. Nucleus 3, 172-186. (2012)
Rashmi R.N., Eckes B., Glöckner G., Groth M., Muller R., Munck M., Neumann S., Gloy J., Sellin L., Walz G., Schneider M., Karakesisoglou I., Eichinger L., and Noegel A.A.
