Centrosome and Spindle Assembly Checkpoint Loss Leads to Neural Apoptosis and Reduced Brain Size

Overview

Journal J Cell Biol

Specialty Cell Biology

Date 2017 Mar 30

PMID 28351851

Citations 21

Authors

John S Poulton

John C Cuningham

Mark Peifer

Affiliations

Soon will be listed here.

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 in found 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.

Citing Articles

The spindle assembly checkpoint and the spatial activation of Polo kinase determine the duration of cell division and prevent tumor formation.

Gallaud E, Richard-Parpaillon L, Bataille L, Pascal A, Metivier M, Archambault V PLoS Genet. 2022; 18(4):e1010145.

PMID: 35377889 PMC: 9009772. DOI: 10.1371/journal.pgen.1010145.

Traip controls mushroom body size by suppressing mitotic defects.

ONeill R, Rusan N Development. 2022; 149(7).

PMID: 35297981 PMC: 8995085. DOI: 10.1242/dev.199987.

Mutations in Drosophila tRNA processing factors cause phenotypes similar to Pontocerebellar Hypoplasia.

Schmidt C, Min L, McVay M, Giusto J, Brown J, Salzler H Biol Open. 2022; 11(3).

PMID: 35132432 PMC: 8935212. DOI: 10.1242/bio.058928.

Biallelic mutations cause microcephaly, developmental delay, and variable effects on cohesion and chromosome segregation.

Carvalhal S, Bader I, Rooimans M, Oostra A, Balk J, Feichtinger R Sci Adv. 2022; 8(3):eabk0114.

PMID: 35044816 PMC: 8769543. DOI: 10.1126/sciadv.abk0114.

Altered cleavage plane orientation with increased genomic aneuploidy produced by receptor-mediated lysophosphatidic acid (LPA) signaling in mouse cerebral cortical neural progenitor cells.

McDonald W, Miyamoto K, Rivera R, Kennedy G, Almeida B, Kingsbury M Mol Brain. 2020; 13(1):169.

PMID: 33317583 PMC: 7734743. DOI: 10.1186/s13041-020-00709-y.

References

Caussinus E, Gonzalez C . Induction of tumor growth by altered stem-cell asymmetric division in Drosophila melanogaster. Nat Genet. 2005; 37(10):1125-9. DOI: 10.1038/ng1632. View

Buffin E, Lefebvre C, Huang J, Gagou M, Karess R . Recruitment of Mad2 to the kinetochore requires the Rod/Zw10 complex. Curr Biol. 2005; 15(9):856-61. DOI: 10.1016/j.cub.2005.03.052. View

Roberts D, Pronobis M, Alexandre K, Rogers G, Poulton J, Schneider D . Defining components of the ß-catenin destruction complex and exploring its regulation and mechanisms of action during development. PLoS One. 2012; 7(2):e31284. PMC: 3281067. DOI: 10.1371/journal.pone.0031284. View

Wang C, Li S, Januschke J, Rossi F, Izumi Y, Garcia-Alvarez G . An ana2/ctp/mud complex regulates spindle orientation in Drosophila neuroblasts. Dev Cell. 2011; 21(3):520-33. DOI: 10.1016/j.devcel.2011.08.002. View

Chatterjee N, Bohmann D . A versatile ΦC31 based reporter system for measuring AP-1 and Nrf2 signaling in Drosophila and in tissue culture. PLoS One. 2012; 7(4):e34063. PMC: 3324472. DOI: 10.1371/journal.pone.0034063. View

Orr B, Bousbaa H, Sunkel C . Mad2-independent spindle assembly checkpoint activation and controlled metaphase-anaphase transition in Drosophila S2 cells. Mol Biol Cell. 2006; 18(3):850-63. PMC: 1805101. DOI: 10.1091/mbc.e06-07-0587. View

Rahmani Z, Gagou M, Lefebvre C, Emre D, Karess R . Separating the spindle, checkpoint, and timer functions of BubR1. J Cell Biol. 2009; 187(5):597-605. PMC: 2806589. DOI: 10.1083/jcb.200905026. View

Betschinger J, Mechtler K, Knoblich J . Asymmetric segregation of the tumor suppressor brat regulates self-renewal in Drosophila neural stem cells. Cell. 2006; 124(6):1241-53. DOI: 10.1016/j.cell.2006.01.038. View

Gatti M, Baker B . Genes controlling essential cell-cycle functions in Drosophila melanogaster. Genes Dev. 1989; 3(4):438-53. DOI: 10.1101/gad.3.4.438. View

10.

Genin A, Desir J, Lambert N, Biervliet M, Aa N, Pierquin G . Kinetochore KMN network gene CASC5 mutated in primary microcephaly. Hum Mol Genet. 2012; 21(24):5306-17. DOI: 10.1093/hmg/dds386. View

11.

Wakefield J, Huang J, Raff J . Centrosomes have a role in regulating the destruction of cyclin B in early Drosophila embryos. Curr Biol. 2000; 10(21):1367-70. DOI: 10.1016/s0960-9822(00)00776-4. View

12.

Sunkel C, Glover D . polo, a mitotic mutant of Drosophila displaying abnormal spindle poles. J Cell Sci. 1988; 89 ( Pt 1):25-38. DOI: 10.1242/jcs.89.1.25. View

13.

Ripoll P, Pimpinelli S, Valdivia M, Avila J . A cell division mutant of Drosophila with a functionally abnormal spindle. Cell. 1985; 41(3):907-12. DOI: 10.1016/s0092-8674(85)80071-4. View

14.

Bertet C, Li X, Erclik T, Cavey M, Wells B, Desplan C . Temporal patterning of neuroblasts controls Notch-mediated cell survival through regulation of Hid or Reaper. Cell. 2014; 158(5):1173-1186. PMC: 4153738. DOI: 10.1016/j.cell.2014.07.045. View

15.

Urbach R, Technau G . Molecular markers for identified neuroblasts in the developing brain of Drosophila. Development. 2003; 130(16):3621-37. DOI: 10.1242/dev.00533. View

16.

Nigg E, cajanek L, Arquint C . The centrosome duplication cycle in health and disease. FEBS Lett. 2014; 588(15):2366-72. DOI: 10.1016/j.febslet.2014.06.030. View

17.

Gogendeau D, Siudeja K, Gambarotto D, Pennetier C, Bardin A, Basto R . Aneuploidy causes premature differentiation of neural and intestinal stem cells. Nat Commun. 2015; 6:8894. PMC: 4660207. DOI: 10.1038/ncomms9894. View

18.

Madigan J, Chotkowski H, Glaser R . DNA double-strand break-induced phosphorylation of Drosophila histone variant H2Av helps prevent radiation-induced apoptosis. Nucleic Acids Res. 2002; 30(17):3698-705. PMC: 137418. DOI: 10.1093/nar/gkf496. View

19.

Milan M, Clemente-Ruiz M, Dekanty A, Muzzopappa M . Aneuploidy and tumorigenesis in Drosophila. Semin Cell Dev Biol. 2014; 28:110-5. DOI: 10.1016/j.semcdb.2014.03.014. View

20.

Musacchio A . The Molecular Biology of Spindle Assembly Checkpoint Signaling Dynamics. Curr Biol. 2015; 25(20):R1002-18. DOI: 10.1016/j.cub.2015.08.051. View