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

被引：32

作者：

Broix, Loic ^{[1
,2
,3
,4
,5
]}

Asselin, Laure ^{[1
,2
,3
,4
]}

Silva, Carla G. ^{[6
]}

Ivanova, Ekaterina L. ^{[1
,2
,3
,4
]}

Tilly, Peggy ^{[1
,2
,3
,4
]}

Gilet, Johan G. ^{[1
,2
,3
,4
]}

Lebrun, Nicolas ^{[5
]}

Jagline, Helene ^{[1
,2
,3
,4
]}

Muraca, Giuseppe ^{[5
]}

Saillour, Yoann ^{[5
]}

Drouot, Nathalie ^{[1
,2
,3
,4
]}

Reilly, Madeline Louise ^{[7
,8
,9
]}

Francis, Fiona ^{[10
,11
,12
]}

Benmerah, Alexandre ^{[8
,9
]}

Bahi-Buisson, Nadia ^{[7
,8
]}

Belvindrah, Richard ^{[10
,11
,12
]}

Nguyen, Laurent ^{[6
]}

Godin, Juliette D. ^{[1
,2
,3
,4
]}

Chelly, Jamel ^{[1
,2
,3
,4
,13
]}

Hinckelmann, Maria-Victoria ^{[1
,2
,3
,4
]}

机构：

[1] Inst Genet & Biol Mol & Cellulaire, F-67400 Illkirch Graffenstaden, France

[2] CNRS, U7104, F-67400 Illkirch Graffenstaden, France

[3] INSERM, U964, F-67400 Illkirch Graffenstaden, France

[4] Univ Strasbourg, F-67400 Illkirch Graffenstaden, France

[5] Paris Descartes Univ, Inst Cochin, INSERM, U1016,CNRS,U8104, F-75000 Paris, France

[6] Univ Liege, GIGA Neurosci, CHU Sart Tilman, B-4000 Liege, Belgium

[7] Paris Diderot Univ, F-75013 Paris, France

[8] INSERM, UMR 1163, F-75015 Paris, France

[9] Paris Descartes Sorbonne Paris Cite Univ, Imagine Inst, F-75015 Paris, France

[10] INSERM, UMR S 839, F-75005 Paris, France

[11] Univ Paris 06, Sorbonne Univ, F-75000 Paris, France

[12] Inst Fer Moulin, F-75000 Paris, France

[13] Hop Univ Strasbourg, Serv Diagnost Genet, Hop Civil Strasbourg, F-67000 Strasbourg, France

来源：

HUMAN MOLECULAR GENETICS | 2018年 / 27卷 / 02期

关键词：

INTERKINETIC NUCLEAR MIGRATION; SUPERFAMILY PROTEIN 2A; NEURONAL MIGRATION; NEURAL PROGENITORS; SPINDLE DYNAMICS; RADIAL MIGRATION; PRIMARY CILIA; KIF2A; MUTATIONS; DOUBLECORTIN;

D O I：

10.1093/hmg/ddx384

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：224 / 238

页数：15

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