Ciliogenesis and cell cycle alterations contribute to KIF2A-related malformations of cortical development.
Fiche publication
Date publication
janvier 2018
Journal
Human molecular genetics
Auteurs
Membres identifiés du Cancéropôle Est :
Pr CHELLY Jamel
Tous les auteurs :
Broix L, Asselin L, Silva CG, Ivanova EL, Tilly P, Gilet JG, Lebrun N, Jagline H, Muraca G, Saillour Y, Drouot N, Reilly ML, Francis F, Benmerah A, Bahi-Buisson N, Belvindrah R, Nguyen L, Godin JD, Chelly J, Hinckelmann MV
Lien Pubmed
Résumé
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.
Mots clés
Animals, Brain, metabolism, Cell Cycle, genetics, Cilia, genetics, HeLa Cells, Humans, Kinesin, genetics, Malformations of Cortical Development, genetics, Mice, Microcephaly, metabolism, Microtubules, metabolism, Neurogenesis, Repressor Proteins, genetics, Spindle Apparatus, metabolism, Tubulin, metabolism
Référence
Hum. Mol. Genet.. 2018 Jan 15;27(2):224-238