@article{64c52a67d9984d6696280f2be40b1fcb,
title = "Plk4 Regulates Centriole Asymmetry and Spindle Orientation in Neural Stem Cells",
abstract = "Defects in mitotic spindle orientation (MSO) disrupt the organization of stem cell niches impacting tissue morphogenesis and homeostasis. Mutations in centrosome genes reduce MSO fidelity, leading to tissue dysplasia and causing several diseases such as microcephaly, dwarfism, and cancer. Whether these mutations perturb spindle orientation solely by affecting astral microtubule nucleation or whether centrosome proteins have more direct functions in regulating MSO is unknown. To investigate this question, we analyzed the consequences of deregulating Plk4 (the master centriole duplication kinase) activity in Drosophila asymmetrically dividing neural stem cells. We found that Plk4 functions upstream of MSO control, orchestrating centriole symmetry breaking and consequently centrosome positioning. Mechanistically, we show that Plk4 acts through Spd2 phosphorylation, which induces centriole release from the apical cortex. Overall, this work not only reveals a role for Plk4 in regulating centrosome function but also links the centrosome biogenesis machinery with the MSO apparatus. Mitotic spindle orientation is tightly regulated during development and adulthood to maintain tissue organization and homeostasis. Spindle orientation requires the coordination between centrosomes and cortical cues. Gambarotto et al. report that the centrosome components Plk4 and Spd2 regulate centrosome asymmetry in interphase to influence spindle positioning in mitosis.",
keywords = "Plk4, Spd2, centrosome positioning, centrosomes, spindle orientation, symmetry breaking",
author = "Davide Gambarotto and Carole Pennetier and Ryniawec, {John M.} and Buster, {Daniel W.} and Delphine Gogendeau and Alix Goupil and Maddalena Nano and Anthony Simon and Damien Blanc and Victor Racine and Yuu Kimata and Rogers, {Gregory C.} and Renata Basto",
note = "Funding Information: We dedicate this work to the memory of Giuseppe Boccia. We thank J. Raff, Y. Bellaiche, T. Lee, C. Doe, the Bloomington Stock Center, and BestGene for stocks and reagents; L. Sengmanivong, V. Fraisier, and L. Leconte of the NIC at the IC for valuable help with microscopy; P. Maiuri and M. Rujano for help with data analysis; V. Marthiens, D. Vargas, S. Gemble, O. Goudiam, A. Echard, M. Piel, A. Audibert, J. Azimzadeh, M. H. Verlhac, M. Bornens, J. Raff, and C. Gonzalez for discussions and/or critical comments on the manuscript. Financial support from an ERC starting grant CentroStemCancer 242598, a FRM installation and ATIP grants, the Institut Curie and CNRS. G.C.R. is grateful for support from NCI P30CA23074 and NIGMS R01 GM110166 and GM126035. D.G. was supported by PhD fellowships from IC and FRM. The Basto laboratory is a member of the Labex CelTisPhyBio, D.G. and R.B. conceived the project, analyzed the data, and, together with G.C.R. wrote the manuscript. D.G. performed most of the experimental procedures. C.P. generated tools and most of the transgenic fly stocks. J.M.R, D.W.B. and G.C.R. conceived and performed kinase assays, mass spectrometry, and S2 cell experiments. D.G. generated Plk4WT transgenic fly stocks. A.S. helped with the maintenance of fly stocks, crosses, and dissection, and D.-B. and V.R. identified the methodology used to track centrosome or centriole behavior in time-lapse movies and the representation of their dynamics. Y.K. shared unpublished data. A.G. and M.N. helped R.B. to set up the live imaging of some fly strains. R.B. supervised the project. The authors declare no competing interests. Funding Information: We dedicate this work to the memory of Giuseppe Boccia. We thank J. Raff, Y. Bellaiche, T. Lee, C. Doe, the Bloomington Stock Center, and BestGene for stocks and reagents; L. Sengmanivong, V. Fraisier, and L. Leconte of the NIC at the IC for valuable help with microscopy; P. Maiuri and M. Rujano for help with data analysis; V. Marthiens, D. Vargas, S. Gemble, O. Goudiam, A. Echard, M. Piel, A. Audibert, J. Azimzadeh, M. H. Verlhac, M. Bornens, J. Raff, and C. Gonzalez for discussions and/or critical comments on the manuscript. Financial support from an ERC starting grant CentroStemCancer 242598 , a FRM installation and ATIP grants, the Institut Curie and CNRS . G.C.R. is grateful for support from NCI P30CA23074 and NIGMS R01 GM110166 and GM126035 . D.G. was supported by PhD fellowships from IC and FRM. The Basto laboratory is a member of the Labex CelTisPhyBio Publisher Copyright: {\textcopyright} 2019 The Authors",
year = "2019",
month = jul,
day = "1",
doi = "10.1016/j.devcel.2019.04.036",
language = "English (US)",
volume = "50",
pages = "11--24.e10",
journal = "Developmental Cell",
issn = "1534-5807",
publisher = "Cell Press",
number = "1",
}