DIAPH3 deficiency links microtubules to mitotic errors, defective neurogenesis, and brain dysfunction
- Université catholique de Louvain, Belgium
- Université Catholique de Louvain, Belgium
- HBKU, Qatar
Abstract
Diaphanous (DIAPH) 3 is a member of the formin proteins that have the capacity to nucleate and elongate actin filaments and therefore, to remodel the cytoskeleton. DIAPH3 is essential for cytokinesis as its dysfunction impairs the contractile ring and produces multinucleated cells. Here, we report that DIAPH3 localizes at the centrosome during mitosis and regulates the assembly and bi-polarity of the mitotic spindle. DIAPH3-deficient cells display disorganized cytoskeleton, and multipolar spindles. DIAPH3-deficiency disrupts the expression and/or stability of several proteins including the kinetochore-associated protein SPAG5. DIAPH3 and SPAG5 have similar expression patterns in the developing brain and overlapping subcellular localization during mitosis. Knockdown of SPAG5 phenocopies the DIAPH3 deficiency, whereas its overexpression rescues the DIAHP3 knockdown phenotype. Conditional inactivation of Diaph3 in mouse cerebral cortex profoundly disrupts neurogenesis depleting cortical progenitors and neurons; and leading to cortical malformation and autistic-like behavior. Our data uncover uncharacterized functions of DIAPH3 and provide evidence that this protein belongs to a molecular toolbox that links microtubule dynamics during mitosis to aneuploidy, cell death, fate determination defects, and cortical malformation.
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All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for all figures
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Funding
Fonds De La Recherche Scientifique - FNRS (FNRS PDR T00075.15)
- Fadel Tissir
Fonds De La Recherche Scientifique - FNRS (FNRS PDR T0236.20)
- Fadel Tissir
Fonds De La Recherche Scientifique - FNRS (EOS 30913351)
- Fadel Tissir
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal procedures were carried out in accordance with European guidelines and approved by the animal ethics committee of the Université Catholique de Louvain (permit number 2019/UCL/MD/006
Copyright
© 2021, Lau et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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DIAPH3 deficiency links microtubules to mitotic errors, defective neurogenesis, and brain dysfunction
eLife 10:e61974.
https://doi.org/10.7554/eLife.61974
