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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 publication

DOI

10.15252/embr.201541823

Type

Journal article

Journal

EMBO Rep

Publication Date

10/2016

Volume

17

Pages

1396 - 1409

Keywords

astral microtubules, asymmetric division, microcephaly, mitotic spindle orientation, neurogenesis, Animals, Brain, Calmodulin-Binding Proteins, Cell Line, Drosophila, Dynactin Complex, Female, Gene Expression Regulation, Gene Silencing, HeLa Cells, Humans, Intracellular Signaling Peptides and Proteins, Mice, Mice, Knockout, Microtubules, Mitosis, Nerve Tissue Proteins, Protein Binding, Protein Stability, Protein Transport, Protein-Serine-Threonine Kinases, RNA Interference, Spindle Apparatus