title: Centrosome and spindle assembly checkpoint loss leads to neural apoptosis and reduced brain size.
abstract: Accurate mitotic spindle assembly is critical for mitotic fidelity and organismal development. Multiple processes coordinate spindle assembly and chromosome segregation. Two key components are centrosomes and the spindle assembly checkpoint (SAC), and mutations affecting either can cause human microcephaly. In vivo studies inDrosophila melanogasterfound that loss of either component alone is well tolerated in the developing brain, in contrast to epithelial tissues of the imaginal discs. In this study, we reveal that one reason for that tolerance is the compensatory relationship between centrosomes and the SAC. In the absence of both centrosomes and the SAC, brain cells, including neural stem cells, experience massive errors in mitosis, leading to increased cell death, which reduces the neural progenitor pool and severely disrupts brain development. However, our data also demonstrate that neural cells are much more tolerant of aneuploidy than epithelial cells. Our data provide novel insights into the mechanisms by which different tissues manage genome stability and parallels with human microcephaly.
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 peifer@unc.edu poultonj@email.unc.edu.|Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
authors.forename: John S
authors.initials: JS
authors.lastname: Poulton
authors.affiliation: Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
authors.forename: John C
authors.initials: JC
authors.lastname: Cuningham
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 peifer@unc.edu poultonj@email.unc.edu.|Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
authors.forename: Mark
authors.identifier: 0000-0003-1412-3987
authors.initials: M
authors.lastname: Peifer
mesh_terms: D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000473:pathology*; D059447:Cell Cycle Checkpoints; D049109:Cell Proliferation; D018385:Centrosome / Q000378:metabolism*; D004331:Drosophila melanogaster; D007814:Larva / Q000378:metabolism; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000473:pathology*; D008941:Spindle Apparatus / Q000378:metabolism*