Mms19 promotes spindle microtubule assembly in Drosophila neural stem cells.

Mitotic divisions depend on the timely assembly and proper orientation of the mitotic spindle. Malfunctioning of these processes can considerably delay mitosis, thereby compromising tissue growth and homeostasis, and leading to chromosomal instability. Loss of functional Mms19 drastically affects the growth and development of mitotic tissues in Drosophila larvae and we now demonstrate that Mms19 is an important factor that promotes spindle and astral microtubule (MT) growth, and MT stability and bundling. Mms19 function is needed for the coordination of mitotic events and for the rapid progression through mitosis that is characteristic of neural stem cells. Surprisingly, Mms19 performs its mitotic activities through two different pathways. By stimulating the mitotic kinase cascade, it triggers the localization of the MT regulatory complex TACC/Msps (Transforming Acidic Coiled Coil/Minispindles, the homolog of human ch-TOG) to the centrosome. This activity of Mms19 can be rescued by stimulating the mitotic kinase cascade. However, other aspects of the Mms19 phenotypes cannot be rescued in this way, pointing to an additional mechanism of Mms19 action. We provide evidence that Mms19 binds directly to MTs and that this stimulates MT stability and bundling. Author summary: Mitosis is a fundamental process that segregates replicated chromosomes into daughter cells, allowing organ growth and development in multicellular organisms. To properly distribute the genetic material, the mitotic spindle, an organelle consisting of extended microtubules, microtubule motors, and additional microtubule-associated proteins needs to be built in a coordinated, robust, but still dynamic way. Failure to set up these spindles properly leads to chromosomal instability or differentiation defects, and this can lead to tumor formation, reduced organ growth, or lack of specific cell types. Whereas Mms19 protein performs activities unrelated to mitosis, we found that Drosophila Mms19 is also crucial for mitotic progression and organ growth. This led us to discover that Mms19 had been repurposed to also assist in the formation of stable spindle microtubules. By regulating spindle architecture, Mms19 allows neural stem cells to timely progress through mitosis to build the normal brain. Surprisingly, Mms19 exerts its spindle regulatory function again through different activities. It stimulates microtubule assembly through a mitotic kinase cascade consisting of 3 kinases to activate microtubule organizer proteins. Additional evidence suggests that it is capable of interacting with microtubules and promotes microtubule bundling and that this is also important to form a functional mitotic spindle. [ABSTRACT FROM AUTHOR]