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Genetic interaction between PLK1 and downstream MCPH proteins in the control of centrosome asymmetry and cell fate during neural progenitor division


Alteration of centrosome function and dynamics results in major defects during chromosome segregation and is associated with primary autosomal microcephaly (MCPH). Despite the knowledge accumulated in the last few years, why some centrosomal defects specifically affect neural progenitors is not clear. We describe here that the centrosomal kinase PLK1 controls centrosome asymmetry and cell fate in neural progenitors during development. Gain- or loss-of-function mutations in Plk1, as well as deficiencies in the MCPH genes Cdk5rap2 (MCPH3) and Cep135 (MCPH8), lead to abnormal asymmetry in the centrosomes carrying the mother and daughter centriole in neural progenitors. However, whereas loss of MCPH proteins leads to increased centrosome asymmetry and microcephaly, deficient PLK1 activity results in reduced asymmetry and increased expansion of neural progenitors and cortical growth during mid-gestation. The combination of PLK1 and MCPH mutations results in increased microcephaly accompanied by more aggressive centrosomal and mitotic abnormalities. In addition to highlighting the delicate balance in the level and activity of centrosomal regulators, these data suggest that human PLK1, which maps to 16p12.1, may contribute to the neurodevelopmental defects associated with 16p11.2–p12.2 microdeletions and microduplications in children with developmental delay and dysmorphic features.

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Fig. 1: PLK1 deregulation promotes microcephaly in mouse embryos.
Fig. 2: PLK1 orchestrates progenitor-division mode and cell fate during neurodevelopment.
Fig. 3: Deficient PLK1 activity alters cortical neurodevelopment in mouse embryos.
Fig. 4: Centrosomal defects in Cdk5rap2- and Cep135-deficient mice.
Fig. 5: Cdk5rap2 and Plk1 genetically interact to induce microcephaly in mice.
Fig. 6: PLK1 and CDK5RAP2 display opposite forces in the control of centrosome asymmetry.

Data availability

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.


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We thank members of the Comparative Pathology and Sagrario Ortega and the members of the Mouse Genome Editing Unit at CNIO for excellent technical support.


JGM and DMA received predoctoral contracts from the Ministry of Education of Spain (FPI grant BES-2016-077901). This work was supported by Grant PID2019-104763RB-I00 and Ramón y Cajal contract (RYC-2014-15991), both from MINECO/AEI/FEDER (EU) to EP; and grants from the European Commission Seventh Framework Programme (ERA-NET NEURON8-Full-815-094), AEI-MICIU/FEDER (RTI2018-095582-B-I00 and RED2018-102723-T), and the iLUNG programme from the Comunidad de Madrid (B2017/BMD-3884) to MM. CNIO is a Severo Ochoa Center of Excellence (AEI-MICIU CEX2019-000891-S).

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JGM performed most in vitro and in vivo assays with the help of AWC and JG. PS and GdC generated and contributed to the analysis of Plk1 models. JG and DM participated in the confocal analysis of images. GG and FM participated in the quantitative analysis of skulls. EMP, PS, and GdC contributed to the characterization of the effect of PLK1 inhibitors. MM supervised the project. All authors analyzed data, and JGM and MM wrote the paper with the help of AWC, JG and EMP.

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Correspondence to Marcos Malumbres.

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The authors declare no competing interests.

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The animals were observed on a daily basis, and sick mice were humanely euthanized in accordance with the Guidelines for Humane End-points for Animals Used in Biomedical Research (Directive 2010/63/EU of the European Parliament and Council and the Recommendation 2007/526/CE of the European Commission). All animal protocols were approved by the Committee for Animal Care and Research of the Instituto de Salud Carlos III and the Comunidad de Madrid (Madrid, Spain).

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González-Martínez, J., Cwetsch, A.W., Gilabert-Juan, J. et al. Genetic interaction between PLK1 and downstream MCPH proteins in the control of centrosome asymmetry and cell fate during neural progenitor division. Cell Death Differ 29, 1474–1485 (2022).

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