Amphiphysin: a key hub for nuclear positioning
The BIN1 gene (encoding for amphiphysin) is regulating the positioning of the nucleus through several proteins related to the cytoskeleton: amphiphysin binds to nesprin, an actin interactor, and directly to actin filaments. Amphiphysin also partners with CLIP170, a microtubule-associated protein.
Oct. 26, 2015
The place of the nucleus is important for the organization of cells and tissue development. This positioning is altered in many diseases such as centronuclear myopathies. In a study published on October 26th in Developmental Cell, the teams of Jocelyn Laporte and Michel Labouesse, in collaboration with those of Edgar Gomes in Lisbon and Vincent Gache in Lyon, have just identified a key player in the nucleus positioning mechanism: the amphiphysin.
When the nucleus is mis-positioned
The position of the nucleus within a cell is not random but is actually key to proper cellular function, e.g. for the formation of multinucleated muscle fibers nuclei should be distributed in an optimal and polarized way. Muscle fibers indeed contain several hundred of nuclei normally at the cell periphery; these nuclei are mis-placed in several muscle diseases such as centronuclear myopathy which, as the name implies, is characterized by abnormal centralization of nuclei. The mechanisms that regulate the correct positioning of nuclei were barely known to date.
A small worm to study a human disease
Mutations in BIN1, the gene encoding amphiphysin, are responsible for centronuclear myopathy. It was so far unclear whether this mis-position of the nuclei was a primary or secondary consequence of amphiphysin defects. The scientists have used a tiny animal model, the nematode worm C. elegans, which also displays nuclei mis-positioning following mutations in amphiphysin. They have demonstrated that amphiphysin would link the nucleus with the cytoskeleton, a kind of skeleton that allows the proper organization and shape of the cell.
Amphiphysin and the cytoskeleton
In this study, the scientists discover that amphiphysin acts on the two major cytoskeletal networks, actin and microtubules. On the one hand, amphiphysin binds to actin filaments via nesprin, a protein anchored in the nuclear envelope. On the other, it is associated with the microtubule binding protein CLIP170. Amphiphysin is therefore an essential link between the nuclear envelope and cytoskeletal networks. Primary defects of nesprin also lead to a myopathy, the Emery-Dreifuss Muscular Dystrophy. The amphiphysin-nesprin complex thus connects two myopathies in a common molecular mechanism, suggesting that similar therapeutic approaches may be applicable to these myopathies.
Through its actions on the cytoskeleton, amphiphysin has a key role in positioning the nucleus within the cell, a mechanism conserved throughout evolution (in the nematode, mouse and Human) and altered in several myopathies. These results offer a first molecular explanation for this pathological feature and provide insight into the mechanisms leading to these diseases. However, the link between the nucleus position and the muscle weakness, also characteristic of these diseases, is not yet understood.