ASPM and CITK regulate spindle orientation by affecting the dynamics of astral microtubules

Marta Gai, Federico T. Bianchi, Cristiana Vagnoni, Fiammetta Vernì, Silvia Bonaccorsi, Selina Pasquero, Gaia E. Berto, Francesco Sgrò, Alessandra M A Chiotto, Laura Annaratone, Anna Sapino, Anna Bergo, Nicoletta Landsberger, Jacqueline Bond, Wieland B. Huttner, Ferdinando Di Cunto

Research output: Contribution to journalArticle

Abstract

Correct orientation of cell division is considered an important factor for the achievement of normal brain size, as mutations in genes that affect this process are among the leading causes of microcephaly. Abnormal spindle orientation is associated with reduction of the neuronal progenitor symmetric divisions, premature cell cycle exit, and reduced neurogenesis. This mechanism has been involved in microcephaly resulting from mutation of ASPM, the most frequently affected gene in autosomal recessive human primary microcephaly (MCPH), but it is presently unknown how ASPM regulates spindle orientation. In this report, we show that ASPM may control spindle positioning by interacting with citron kinase (CITK), a protein whose loss is also responsible for severe microcephaly in mammals. We show that the absence of CITK leads to abnormal spindle orientation in mammals and insects. In mouse cortical development, this phenotype correlates with increased production of basal progenitors. ASPM is required to recruit CITK at the spindle, and CITK overexpression rescues ASPM phenotype. ASPM and CITK affect the organization of astral microtubules (MT), and low doses of MT-stabilizing drug revert the spindle orientation phenotype produced by their knockdown. Finally, CITK regulates both astral-MT nucleation and stability. Our results provide a functional link between two established microcephaly proteins.

Original languageEnglish
Pages (from-to)1396-1409
Number of pages14
JournalEMBO Reports
Volume17
Issue number10
DOIs
Publication statusPublished - Oct 1 2016

Fingerprint

Microtubules
Microcephaly
Mammals
Phenotype
Genes
Cells
Mutation
Neurogenesis
Cell Division
Insects
citron-kinase
Brain
Cell Cycle
Proteins
Nucleation
Pharmaceutical Preparations

Keywords

  • astral microtubules
  • asymmetric division
  • microcephaly
  • mitotic spindle orientation
  • neurogenesis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Gai, M., Bianchi, F. T., Vagnoni, C., Vernì, F., Bonaccorsi, S., Pasquero, S., ... Di Cunto, F. (2016). ASPM and CITK regulate spindle orientation by affecting the dynamics of astral microtubules. EMBO Reports, 17(10), 1396-1409. https://doi.org/10.15252/embr.201541823

ASPM and CITK regulate spindle orientation by affecting the dynamics of astral microtubules. / Gai, Marta; Bianchi, Federico T.; Vagnoni, Cristiana; Vernì, Fiammetta; Bonaccorsi, Silvia; Pasquero, Selina; Berto, Gaia E.; Sgrò, Francesco; Chiotto, Alessandra M A; Annaratone, Laura; Sapino, Anna; Bergo, Anna; Landsberger, Nicoletta; Bond, Jacqueline; Huttner, Wieland B.; Di Cunto, Ferdinando.

In: EMBO Reports, Vol. 17, No. 10, 01.10.2016, p. 1396-1409.

Research output: Contribution to journalArticle

Gai, M, Bianchi, FT, Vagnoni, C, Vernì, F, Bonaccorsi, S, Pasquero, S, Berto, GE, Sgrò, F, Chiotto, AMA, Annaratone, L, Sapino, A, Bergo, A, Landsberger, N, Bond, J, Huttner, WB & Di Cunto, F 2016, 'ASPM and CITK regulate spindle orientation by affecting the dynamics of astral microtubules', EMBO Reports, vol. 17, no. 10, pp. 1396-1409. https://doi.org/10.15252/embr.201541823
Gai M, Bianchi FT, Vagnoni C, Vernì F, Bonaccorsi S, Pasquero S et al. ASPM and CITK regulate spindle orientation by affecting the dynamics of astral microtubules. EMBO Reports. 2016 Oct 1;17(10):1396-1409. https://doi.org/10.15252/embr.201541823
Gai, Marta ; Bianchi, Federico T. ; Vagnoni, Cristiana ; Vernì, Fiammetta ; Bonaccorsi, Silvia ; Pasquero, Selina ; Berto, Gaia E. ; Sgrò, Francesco ; Chiotto, Alessandra M A ; Annaratone, Laura ; Sapino, Anna ; Bergo, Anna ; Landsberger, Nicoletta ; Bond, Jacqueline ; Huttner, Wieland B. ; Di Cunto, Ferdinando. / ASPM and CITK regulate spindle orientation by affecting the dynamics of astral microtubules. In: EMBO Reports. 2016 ; Vol. 17, No. 10. pp. 1396-1409.
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