Ciliogenesis and cell cycle alterations contribute to KIF2A-related malformations of cortical development

Human Molecular Genetics
Loïc BroixMaria-Victoria Hinckelmann

Abstract

Genetic findings reported by our group and others showed that de novo missense variants in the KIF2A gene underlie malformations of brain development called pachygyria and microcephaly. Though KIF2A is known as member of the Kinesin-13 family involved in the regulation of microtubule end dynamics through its ATP dependent MT-depolymerase activity, how KIF2A variants lead to brain malformations is still largely unknown. Using cellular and in utero electroporation approaches, we show here that KIF2A disease-causing variants disrupts projection neuron positioning and interneuron migration, as well as progenitors proliferation. Interestingly, further dissection of this latter process revealed that ciliogenesis regulation is also altered during progenitors cell cycle. Altogether, our data suggest that deregulation of the coupling between ciliogenesis and cell cycle might contribute to the pathogenesis of KIF2A-related brain malformations. They also raise the issue whether ciliogenesis defects are a hallmark of other brain malformations, such as those related to tubulins and MT-motor proteins variants.

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Citations

Nov 6, 2018·Human Molecular Genetics·Madeline Louise ReillyAlexandre Benmerah
Feb 6, 2019·Biology of the Cell·Madeline Louise Reilly, Alexandre Benmerah
Jun 10, 2019·Biology of the Cell·Sophie ThomasAlexandre Benmerah
Sep 23, 2020·Developmental Biology·Mia J KonjikusicJohn B Wallingford
Apr 3, 2021·Alzheimer's & Dementia : the Journal of the Alzheimer's Association·Dmitry ProkopenkoRudolph E Tanzi

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