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

[en] 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.

Disciplines :

Neurology

Author, co-author :

Broix, Loic

Asselin, Laure

Gomes Da Silva, Carla ; Université de Liège > GIGA - Neurosciences

Ivanova, Ekaterina L.

Tilly, Peggy

Gilet, Johan G.

Lebrun, Nicolas

Jagline, Helene

Muraca, Giuseppe

Saillour, Yoann

More authors (10 more)

Language :

English

Title :

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

Publication date :

2018

Journal title :

Human Molecular Genetics

ISSN :

0964-6906

eISSN :

1460-2083

Publisher :

Oxford University Press, United Kingdom

Peer reviewed :

Peer Reviewed verified by ORBi

Commentary :

Available on ORBi :

since 04 January 2018

Statistics

Number of views

52 (7 by ULiège)

Number of downloads

3 (3 by ULiège)

More statistics

Scopus citations^®

Scopus citations^®
without self-citations

OpenCitations

Bibliography

Desikan, R.S. and Barkovich, A.J. (2016) Malformations of cortical development. Ann. Neurol., 80, 797-810
des Portes, V., Francis, F., Pinard, J.M., Desguerre, I., Moutard, M.L., Snoeck, I., Meiners, L.C., Capron, F., Cusmai, R. and Ricci, S. (1998) doublecortin is the major gene causing X-linked subcortical laminar heterotopia (SCLH). Hum. Mol. Genet., 7, 1063-1070
Reiner, O., Carrozzo, R., Shen, Y., Wehnert, M., Faustinella, F., Dobyns, W.B., Caskey, C.T. and Ledbetter, D.H. (1993) Isolation of a Miller-Dieker lissencephaly gene containing G protein beta-subunit-like repeats. Nature, 364, 717-721
Gleeson, J.G., Allen, K.M., Fox, J.W., Lamperti, E.D., Berkovic, S., Scheffer, I., Cooper, E.C., Dobyns, W.B., Minnerath, S.R., Ross, M.E. et al. (1998) Doublecortin, a brain-specific gene mutated in human X-linked lissencephaly and double cortex syndrome, encodes a putative signaling protein. Cell, 92, 63-72
Bahi-Buisson, N., Souville, I., Fourniol, F.J., Toussaint, A., Moores, C.A., Houdusse, A., Lemaitre, J.Y., Poirier, K., Khalaf-Nazzal, R., Hully, M. et al. (2013) New insights into genotype-phenotype correlations for the doublecortinrelated lissencephaly spectrum. Brain, 136, 223-244
Keays, D.A., Tian, G., Poirier, K., Huang, G.-J., Siebold, C., Cleak, J., Oliver, P.L., Fray, M., Harvey, R.J., Molnár, Z. et al. (2007) Mutations in alpha-tubulin cause abnormal neuronal migration in mice and lissencephaly in humans. Cell, 128, 45-57
Jaglin, X.H. and Chelly, J. (2009) Tubulin-related cortical dysgeneses: microtubule dysfunction underlying neuronal migration defects. Trends Genet., 25, 555-566
Poirier, K., Saillour, Y., Bahi-Buisson, N., Jaglin, X.H., Fallet-Bianco, C., Nabbout, R., Castelnau-Ptakhine, L., Roubertie, A., Attie-Bitach, T., Desguerre, I. et al. (2010) Mutations in the neuronal ß-tubulin subunit TUBB3 result in malformation of cortical development and neuronal migration defects. Hum. Mol. Genet., 19, 4462-4473
Breuss, M., Heng, J.I.-T., Poirier, K., Tian, G., Jaglin, X.H., Qu, Z., Braun, A., Gstrein, T., Ngo, L., Haas, M. et al. (2012) Mutations in the b-tubulin gene TUBB5 cause microcephaly with structural brain abnormalities. Cell Rep., 2, 1554-1562
Poirier, K., Lebrun, N., Broix, L., Tian, G., Saillour, Y., Boscheron, C., Parrini, E., Valence, S., Pierre, B. Saint, Oger, M. et al. (2013) Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly. Nat. Genet., 45, 639-647
Bahi-Buisson, N., Poirier, K., Fourniol, F., Saillour, Y., Valence, S., Lebrun, N., Hully, M., Bianco, C.F., Boddaert, N., Elie, C. et al. (2014) The wide spectrum of tubulinopathies: what are the key features for the diagnosis?. Brain, 137, 1676-1700
Tischfield, M.A., Cederquist, G.Y., Gupta, M.L. and Engle, E.C. (2011) Phenotypic spectrum of the tubulin-related disorders and functional implications of disease-causing mutations. Curr. Opin. Genet. Dev., 21, 286-294
Breuss, M., Fritz, T., Gstrein, T., Chan, K., Ushakova, L., Yu, N., Vonberg, F.W., Werner, B., Elling, U. and Keays, D.A. (2016) Mutations in the murine homologue of TUBB5 cause microcephaly by perturbing cell cycle progression and inducing p53-associated apoptosis. Development, 143, 1126-1133
Saillour, Y., Broix, L., Bruel-Jungerman, E., Lebrun, N., Muraca, G., Rucci, J., Poirier, K., Belvindrah, R., Francis, F. and Chelly, J. (2014) Beta tubulin isoforms are not interchangeable for rescuing impaired radial migration due to Tubb3 knockdown. Hum. Mol. Genet., 23, 1516-1526
Cavallin, M., Bijlsma, E.K., El Morjani, A., Moutton, S., Peeters, E.A.J., Maillard, C., Pedespan, J.M., Guerrot, A.-M., Drouin-Garaud, V., Coubes, C. et al. (2017) Recurrent KIF2A mutations are responsible for classic lissencephaly. Neurogenetics, 18, 73-79
Tian, G., Cristancho, A.G., Dubbs, H.A., Liu, G.T., Cowan, N.J. and Goldberg, E.M. (2016) A patient with lissencephaly, developmental delay, and infantile spasms, due to de novo heterozygous mutation of KIF2A. Mol. Genet. Genomic Med., 4, 599-603
Desai, A., Verma, S., Mitchison, T.J. and Walczak, C.E. (1999) Kin I kinesins are microtubule-destabilizing enzymes. Cell, 96, 69-78
Walczak, C.E., Gayek, S. and Ohi, R. (2013) Microtubule-depolymerizing kinesins. Annu. Rev. Cell Dev. Biol., 29, 417-441
Ems-McClung, S.C. and Walczak, C.E. (2010) Kinesin-13s in mitosis: Key players in the spatial and temporal organization of spindle microtubules. Semin. Cell Dev. Biol., 21, 276-282
Jang, C.-Y., Wong, J., Coppinger, J.A., Seki, A., Yates, J.R. and Fang, G. (2008) DDA3 recruits microtubule depolymerase Kif2a to spindle poles and controls spindle dynamics and mitotic chromosome movement. J. Cell Biol., 181, 255-267
Ganem, N.J., Upton, K. and Compton, D.A. (2005) Efficient mitosis in human cells lacking poleward microtubule flux. Curr. Biol., 15, 1827-1832
Uehara, R., Tsukada, Y., Kamasaki, T., Poser, I., Yoda, K., Gerlich, D.W. and Goshima, G. (2013) Aurora B and Kif2A control microtubule length for assembly of a functional central spindle during anaphase. J. Cell Biol., 202, 623-636
Kwon, H.J., Park, J.E., Song, H. and Jang, C.-Y. (2016) DDA3 and Mdp3 modulate Kif2a recruitment onto the mitotic spindle to control minus-end spindle dynamics. J. Cell Sci., 129, 2719-2725
Manning, A.L., Ganem, N.J., Bakhoum, S.F., Wagenbach, M., Wordeman, L. and Compton, D.A. (2007) The kinesin-13 proteins Kif2a, Kif2b, and Kif2c/MCAK have distinct roles during mitosis in human cells. Mol. Biol. Cell, 18, 2970-2979
Homma, N., Takei, Y., Tanaka, Y., Nakata, T., Terada, S., Kikkawa, M., Noda, Y. and Hirokawa, N. (2003) Kinesin superfamily protein 2A (KIF2A) functions in suppression of collateral branch extension. Cell, 114, 229-239
Maor-Nof, M., Homma, N., Raanan, C., Nof, A., Hirokawa, N. and Yaron, A. (2013) Axonal pruning is actively regulated by the microtubule-destabilizing protein kinesin superfamily protein 2A. Cell Rep., 3, 971-977
Noda, Y., Sato-Yoshitake, R., Kondo, S., Nangaku, M. and Hirokawa, N. (1995) KIF2 is a new microtubule-based anterograde motor that transports membranous organelles distinct from those carried by kinesin heavy chain or KIF3A/B. J. Cell Biol., 129, 157-167
Miyamoto, T., Hosoba, K., Ochiai, H., Royba, E., Izumi, H., Sakuma, T., Yamamoto, T., Dynlacht, B.D. and Matsuura, S. (2015) The Microtubule-Depolymerizing Activity of a Mitotic Kinesin Protein KIF2A Drives Primary Cilia Disassembly Coupled with Cell Proliferation. Cell Rep., 10, 664-673
Bilgüvar, K., Öztürk, A.K., Louvi, A., Kwan, K.Y., Choi, M., Tatli, B., Yalnizóglu, D., Tüysüz, B., Çáglayan, A.O., Gökben, S. et al. (2010) Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Nature, 467, 207-210
Santos, D.V.M. dos (2012) Regulation of neural stem cell proliferation and differentiation by apoptosis-relevant factors. 5, 1-17
Barry, D.S., Pakan, J.M.P. and McDermott, K.W. (2014) Radial glial cells: key organisers in CNS development. Int. J. Biochem. Cell Biol., 46, 76-79
Marín, O., Valiente, M., Ge, X. and Tsai, L.-H. (2010) Guiding neuronal cell migrations. Cold Spring Harb. Perspect. Biol., 2, a001834
Fietz, S.A. and Huttner, W.B. (2011) Cortical progenitor expansion, self-renewal and neurogenesis-a polarized perspective. Curr. Opin. Neurobiol., 21, 23-35
Shitamukai, A. and Matsuzaki, F. (2012) Control of asymmetric cell division of mammalian neural progenitors. Dev. Growth Differ., 54, 277-286
Ganem, N.J. and Compton, D.A. (2004) The KinI kinesin Kif2a is required for bipolar spindle assembly through a functional relationship with MCAK. J. Cell Biol., 166, 473-478
Valente, E.M., Rosti, R.O., Gibbs, E. and Gleeson, J.G. (2014) Primary cilia in neurodevelopmental disorders. Nat. Rev. Neurol., 10, 27-36
Yang, Y.-T., Wang, C.-L. and Van Aelst, L. (2012) DOCK7 interacts with TACC3 to regulate interkinetic nuclear migration and cortical neurogenesis. Nat. Neurosci., 15, 1201-1210
Schenk, J., Wilsch-Brauninger, M., Calegari, F. and Huttner, W.B. (2009) Myosin II is required for interkinetic nuclear migration of neural progenitors. Proc. Natl. Acad. Sci., 106, 16487-16492
Jaillard, S., Andrieux, J., Plessis, G., Krepischi, A.C.V., Lucas, J., David, V., Le Brun, M., Bertola, D.R., David, A., Belaud-Rotureau, M.-A. et al. (2011) 5q12.1 deletion: Delineation of a phenotype including mental retardation and ocular defects. Am. J. Med. Genet., Part A, 155, 725-731
Moores, C.A. and Milligan, R.A. (2006) Lucky 13-microtubule depolymerisation by kinesin-13 motors. J. Cell Sci., 119, 3905-3913
Jiang, X. and Nardelli, J. (2016) Cellular and molecular introduction to brain development. Neurobiol. Dis., 92, 3-17
Kriegstein, A.R. and Noctor, S.C. (2004) Patterns of neuronal migration in the embryonic cortex. Trends Neurosci., 27, 392-399
Tsai, L.-H. and Gleeson, J.G. (2005) Minireview Nucleokinesis in Neuronal Migration. Neuron, 46, 383-388
Heng, J.I.-T., Chariot, A. and Nguyen, L. (2010) Molecular layers underlying cytoskeletal remodelling during cortical development. Trends Neurosci., 33, 38-47
Bai, J., Ramos, R.L., Ackman, J.B., Thomas, A.M., Lee, R.V. and LoTurco, J.J. (2003) RNAi reveals doublecortin is required for radial migration in rat neocortex. Nat. Neurosci., 6, 1277-1283
Tsai, J.-W., Bremner, K.H. and Vallee, R.B. (2007) Dual subcellular roles for LIS1 and dynein in radial neuronal migration in live brain tissue. Nat. Neurosci., 10, 970-979
Greig, L.C., Woodworth, M.B., Galazo, M.J., Padmanabhan, H. and Macklis, J.D. (2013) Molecular logic of neocortical projection neuron specification, development and diversity. Nat. Rev. Neurosci., 14, 755-769
Izawa, I., Goto, H., Kasahara, K., Inagaki, M., Singla, V., Reiter, J., Nigg, E., Raff, J., Goetz, S., Anderson, K. et al. (2015) Current topics of functional links between primary cilia and cell cycle. Cilia, 4, 12
Doobin, D.J., Kemal, S., Dantas, T.J. and Vallee, R.B. (2016) Severe NDE1-mediated microcephaly results from neural progenitor cell cycle arrests at multiple specific stages. Nat. Commun., 7, 1-14
Li, A., Saito, M., Chuang, J.-Z., Tseng, Y.-Y., Dedesma, C., Tomizawa, K., Kaitsuka, T. and Sung, C.-H. (2011) Ciliary transition zone activation of phosphorylated Tctex-1 controls ciliary resorption, S-phase entry and fate of neural progenitors. Nat. Cell Biol., 13, 402-411
Alcantara, D. and O'Driscoll, M. (2014) Congenital microcephaly. Am. J. Med. Genet. C. Semin. Med. Genet., 166C, 124-139
Jayaraman, D., Kodani, A., Gonzalez, D.M., Mancias, J.D., Mochida, G.H., Vagnoni, C., Johnson, J., Krogan, N., Harper, J.W., Reiter, J.F. et al. (2016) Microcephaly Proteins Wdr62 and Aspm Define a Mother Centriole Complex Regulating Centriole Biogenesis, Apical Complex, and Cell Fate. Neuron, 92, 813-828
Gabriel, E., Wason, A., Ramani, A., Gooi, L.M., Keller, P., Pozniakovsky, A., Poser, I., Noack, F., Telugu, N.S., Calegari, F. et al. (2016) CPAP promotes timely cilium disassembly to maintain neural progenitor pool. embo J., 35, 803-819
Mick, D.U., Rodrigues, R.B., Leib, R.D., Adams, C.M., Chien, A.S., Gygi, S.P. and Nachury, M.V. (2015) Proteomics of Primary Cilia by Proximity Labeling. Dev. Cell, 35, 497-512
Gupta, G.D., Coyaud, É., Gonçalves, J., Mojarad, B.A., Liu, Y., Wu, Q., Gheiratmand, L., Comartin, D., Tkach, J.M., Cheung, S.W.T. et al. (2015) A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface. Cell, 163, 1484-1499
Boldt, K., van Reeuwijk, J., Lu, Q., Koutroumpas, K., Nguyen, T.-M.T., Texier, Y., van Beersum, S.E.C., Horn, N., Willer, J.R., Mans, D.A. et al. (2016) An organelle-specific protein landscape identifies novel diseases and molecular mechanisms. Nat. Commun., 7, 11491