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Mutations in Eml1 lead to ectopic progenitors and neuronal heterotopia in mouse and human

Nature Neuroscience volume 17, pages 923–933 (2014)Cite this article

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Abstract

Neuronal migration disorders such as lissencephaly and subcortical band heterotopia are associated with epilepsy and intellectual disability. DCX, PAFAH1B1 and TUBA1A are mutated in these disorders; however, corresponding mouse mutants do not show heterotopic neurons in the neocortex. In contrast, spontaneously arisen HeCo mice display this phenotype, and our study revealed that misplaced apical progenitors contribute to heterotopia formation. While HeCo neurons migrated at the same speed as wild type, abnormally distributed dividing progenitors were found throughout the cortical wall from embryonic day 13. We identified Eml1, encoding a microtubule-associated protein, as the gene mutated in HeCo mice. Full-length transcripts were lacking as a result of a retrotransposon insertion in an intron. Eml1 knockdown mimicked the HeCo progenitor phenotype and reexpression rescued it. We further found EML1 to be mutated in ribbon-like heterotopia in humans. Our data link abnormal spindle orientations, ectopic progenitors and severe heterotopia in mouse and human.

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Figure 1: HeCo heterotopia and cell accumulation in the dorso-medial regions of developing HeCo cortex.
Figure 2: No changed parameters of migrating cells in HeCo and wild-type mice.
Figure 3: Proliferation defects in HeCo cortex.
Figure 4: Genetic linkage of the HeCo mutation and identification of a retrotransposon in Eml1.
Figure 5: Eml1 brain expression and HeCo and shRNA rescue.
Figure 6: YFP-EML1 in neuronal progenitors in vitro and features of HeCo progenitors.
Figure 7: Mutations in human EML1.
Figure 8: Association of recombinant wild-type and mutant Eml1 with microtubules.

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References

  1. Harding, B. Gray matter heterotopia. in Dysplasias of Cerebral Cortex and Epilepsy, (eds. Guerrini, R. et al.) 81–88 (Lippincott-Raven, Philadelphia, 1996).

  2. Jaglin, X.H. & Chelly, J. Tubulin-related cortical dysgeneses: microtubule dysfunction underlying neuronal migration defects. Trends Genet. 25, 555–566 (2009).

    Article  CAS  PubMed  Google Scholar 

  3. Hirotsune, S. et al. Graded reduction of Pafah1b1 (Lis1) activity results in neuronal migration defects and early embryonic lethality. Nat. Genet. 19, 333–339 (1998).

    Article  CAS  PubMed  Google Scholar 

  4. Corbo, J.C. et al. Doublecortin is required in mice for lamination of the hippocampus but not the neocortex. J. Neurosci. 22, 7548–7557 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kappeler, C. et al. Magnetic resonance imaging and histological studies of corpus callosal and hippocampal abnormalities linked to doublecortin deficiency. J. Comp. Neurol. 500, 239–254 (2007).

    Article  CAS  PubMed  Google Scholar 

  6. Keays, D.A. et al. Mutations in alpha-tubulin cause abnormal neuronal migration in mice and lissencephaly in humans. Cell 128, 45–57 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bai, J. et al. RNAi reveals doublecortin is required for radial migration in rat neocortex. Nat. Neurosci. 6, 1277–1283 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Lee, K.S. et al. A genetic animal model of human neocortical heterotopia associated with seizures. J. Neurosci. 17, 6236–6242 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Munji, R.N., Choe, Y., Li, G., Siegenthaler, J.A. & Pleasure, S.J. Wnt signaling regulates neuronal differentiation of cortical intermediate progenitors. J. Neurosci. 31, 1676–1687 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bilasy, S.E. et al. Dorsal telencephalon–specific RA-GEF-1 knockout mice develop heterotopic cortical mass and commissural fiber defect. Eur. J. Neurosci. 29, 1994–2008 (2009).

    Article  PubMed  Google Scholar 

  11. Cappello, S. et al. A radial glia–specific role of RhoA in double cortex formation. Neuron 73, 911–924 (2012).

    Article  CAS  PubMed  Google Scholar 

  12. Croquelois, A. et al. Characterization of the HeCo mutant mouse: a new model of subcortical band heterotopia associated with seizures and behavioral deficits. Cereb. Cortex 19, 563–575 (2009).

    Article  PubMed  Google Scholar 

  13. Rosen, G.D. et al. Bilateral subcortical heterotopia with partial callosal agenesis in a mouse mutant. Cereb. Cortex 23, 859–872 (2013).

    Article  CAS  PubMed  Google Scholar 

  14. Barkovich, A.J. et al. A developmental and genetic classification for malformations of cortical development: update 2012. Brain 135, 1348–1369 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Konno, D. et al. Neuroepithelial progenitors undergo LGN-dependent planar divisions to maintain self-renewability during mammalian neurogenesis. Nat. Cell Biol. 10, 93–101 (2008).

    Article  CAS  PubMed  Google Scholar 

  16. Chenn, A. & Walsh, C.A. Regulation of cerebral cortical size by control of cell cycle exit in neural precursors. Science 297, 365–369 (2002).

    Article  CAS  PubMed  Google Scholar 

  17. Baust, C. et al. Structure and expression of mobile ETnII retroelements and their coding-competent MusD relatives in the mouse. J. Virol. 77, 11448–11458 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Welker, E. et al. Altered sensory processing in the somatosensory cortex of the mouse mutant barrelless. Science 271, 1864–1867 (1996).

    Article  CAS  PubMed  Google Scholar 

  19. Abdel-Majid, R.M. et al. Loss of adenylyl cyclase I activity disrupts patterning of mouse somatosensory cortex. Nat. Genet. 19, 289–291 (1998).

    Article  CAS  PubMed  Google Scholar 

  20. Hansen, D.V., Lui, J.H., Parker, P.R. & Kriegstein, A.R. Neurogenic radial glia in the outer subventricular zone of human neocortex. Nature 464, 554–561 (2010).

    Article  CAS  PubMed  Google Scholar 

  21. Fietz, S.A. et al. OSVZ progenitors of human and ferret neocortex are epithelial-like and expand by integrin signaling. Nat. Neurosci. 13, 690–699 (2010).

    Article  CAS  PubMed  Google Scholar 

  22. Reillo, I., de Juan Romero, C., García-Cabezas, M.A. & Borrell, V. A role for intermediate radial glia in the tangential expansion of the mammalian cerebral cortex. Cereb. Cortex 21, 1674–1694 (2011).

    Article  PubMed  Google Scholar 

  23. Kelava, I. et al. Abundant occurrence of basal radial glia in the subventricular zone of embryonic neocortex of a lissencephalic primate, the common marmoset Callithrix jacchus. Cereb. Cortex 22, 469–481 (2012).

    Article  PubMed  Google Scholar 

  24. Suprenant, K.A., Dean, K., McKee, J. & Hake, S. EMAP, an echinoderm microtubule-associated protein found in microtubule-ribosome complexes. J. Cell Sci. 104, 445–450 (1993).

    CAS  PubMed  Google Scholar 

  25. Eichenmüller, B., Everley, P., Palange, J., Lepley, D. & Suprenant, K.A. The human EMAP-like protein-70 (ELP70) is a microtubule destabilizer that localizes to the mitotic apparatus. J. Biol. Chem. 277, 1301–1309 (2002).

    Article  CAS  PubMed  Google Scholar 

  26. Brisch, E., Daggett, M.A. & Suprenant, K.A. Cell cycle–dependent phosphorylation of the 77 kDa echinoderm microtubule-associated protein (EMAP) in vivo and association with the p34cdc2 kinase. J. Cell Sci. 109, 2885–2893 (1996).

    CAS  PubMed  Google Scholar 

  27. Pollmann, M. et al. Human EML4, a novel member of the EMAP family, is essential for microtubule formation. Exp. Cell Res. 312, 3241–3251 (2006).

    Article  CAS  PubMed  Google Scholar 

  28. Hueston, J.L. et al. The C. elegans EMAP-like protein, ELP-1 is required for touch sensation and associates with microtubules and adhesion complexes. BMC Dev. Biol. 8, 110 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bechstedt, S. et al. A doublecortin containing microtubule-associated protein is implicated in mechanotransduction in Drosophila sensory cilia. Nat. Commun. 1, 11 (2010).

    Article  CAS  PubMed  Google Scholar 

  30. Tegha-Dunghu, J. et al. EML3 is a nuclear microtubule-binding protein required for the correct alignment of chromosomes in metaphase. J. Cell Sci. 121, 1718–1726 (2008).

    Article  CAS  PubMed  Google Scholar 

  31. Gromley, A. et al. Centriolin anchoring of exocyst and SNARE complexes at the midbody is required for secretory-vesicle-mediated abscission. Cell 123, 75–87 (2005).

    Article  CAS  PubMed  Google Scholar 

  32. Hagemeijer, A. & Graux, C. ABL1 rearrangements in T-cell acute lymphoblastic leukemia. Genes Chromosom. Cancer 49, 299–308 (2010).

    CAS  PubMed  Google Scholar 

  33. Van Karnebeek, C.D. et al. Further delineation of the chromosome 14q terminal deletion syndrome. Am. J. Med. Genet. 110, 65–72 (2002).

    Article  PubMed  Google Scholar 

  34. Ravnan, J.B. et al. Subtelomere FISH analysis of 11688 cases: an evaluation of the frequency and pattern of subtelomere rearrangements in individuals with developmental disabilities. J. Med. Genet. 43, 478–489 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. Richards, M.W. et al. Crystal structure of EML1 reveals the basis for Hsp90 dependence of oncogenic EML4-ALK by disruption of an atypical β-propeller domain. Proc. Natl. Acad. Sci. USA 111, 5195–5200 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Sarkisian, M.R. et al. Trouble making the first move: interpreting arrested neuronal migration in the cerebral cortex. Trends Neurosci. 31, 54–61 (2008).

    Article  CAS  PubMed  Google Scholar 

  37. Cappello, S. et al. Mutations in genes encoding the cadherin receptor-ligand pair DCHS1 and FAT4 disrupt cerebral cortical development. Nat. Genet. 45, 1300–1308 (2013).

    Article  CAS  PubMed  Google Scholar 

  38. Takahashi, T., Goto, T., Miyama, S., Nowakowski, R.S. & Caviness, V.S. Jr. Sequence of neuron origin and neocortical laminar fate: relation to cell cycle of origin in the developing murine cerebral wall. J. Neurosci. 19, 10357–10371 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Stoykova, A., Treichel, D., Hallonet, M. & Gruss, P. Pax6 modulates the dorsoventral patterning of the mammalian telencephalon. J. Neurosci. 20, 8042–8050 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Götz, M., Stoykova, A. & Gruss, P. Pax6 controls radial glia differentiation in the cerebral cortex. Neuron 21, 1031–1044 (1998).

    Article  PubMed  Google Scholar 

  41. Wang, X., Tsai, J.W., Lamonica, B. & Kriegstein, A.R. A new subtype of progenitor cell in the mouse embryonic neocortex. Nat. Neurosci. 14, 555–561 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Shitamukai, A., Konno, D. & Matsuzaki, F. Oblique radial glial divisions in the developing mouse neocortex induce self-renewing progenitors outside the germinal zone that resemble primate outer subventricular zone progenitors. J. Neurosci. 31, 3683–3695 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Houtman, S.H., Rutteman, M., De Zeeuw, C.I. & French, P.J. Echinoderm microtubule-associated protein like protein 4, a member of the echinoderm microtubule-associated protein family, stabilizes microtubules. Neuroscience 144, 1373–1382 (2007).

    Article  CAS  PubMed  Google Scholar 

  44. Kosodo, Y. et al. Asymmetric distribution of the apical plasma membrane during neurogenic divisions of mammalian neuroepithelial cells. EMBO J. 23, 2314–2324 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Dubreuil, V., Marzesco, A.M., Corbeil, D., Huttner, W.B. & Wilsch-Bräuninger, M. Midbody and primary cilium of neural progenitors release extracellular membrane particles enriched in the stem cell marker prominin-1. J. Cell Biol. 176, 483–495 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Weimer, J.M. et al. MARCKS modulates radial progenitor placement, proliferation and organization in the developing cerebral cortex. Development 136, 2965–2975 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Feng, Y. & Walsh, C.A. Mitotic spindle regulation by Nde1 controls cerebral cortical size. Neuron 44, 279–293 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Postiglione, M.P. et al. Mouse inscuteable induces apical-basal spindle orientation to facilitate intermediate progenitor generation in the developing neocortex. Neuron 72, 269–284 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Lancaster, M.A. & Knoblich, J.A. Spindle orientation in mammalian cerebral cortical development. Curr. Opin. Neurobiol. 22, 737–746 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Fitzgerald, M.P., Covio, M. & Lee, K.S. Disturbances in the positioning, proliferation and apoptosis of neural progenitors contribute to subcortical band heterotopia formation. Neuroscience 176, 455–471 (2011).

    Article  CAS  PubMed  Google Scholar 

  51. Niquille, M. et al. Transient neuronal populations are required to guide callosal axons: a role for semaphorin 3C. PLoS Biol. 7, e1000230 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Martynoga, B., Morrison, H., Price, D.J. & Mason, J.O. Foxg1 is required for specification of ventral telencephalon and region-specific regulation of dorsal telencephalic precursor proliferation and apoptosis. Dev. Biol. 283, 113–127 (2005).

    Article  CAS  PubMed  Google Scholar 

  53. Bustin, S.A. et al. The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin. Chem. 55, 611–622 (2009).

    Article  CAS  PubMed  Google Scholar 

  54. Vandesompele, J. et al. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 3, research0034.1–research0034.11 (2002).

    Article  Google Scholar 

  55. Gaspard, N. et al. Generation of cortical neurons from mouse embryonic stem cells. Nat. Protoc. 4, 1454–1463 (2009).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the Inserm Avenir program, the French Agence National de la Recherche (ANR-08-MNP-013 (F.F.), ANR-13-BSV4-0008-01 (F.F.), ANR Blanc 1103-01 (J.C.), projet R11039KK, ANR E-Rare Program, convention 2011-RaARE-012-01) (J.C.), the Fondation Bettencourt Schueller and the Federation pour la recherche sur le cerveau (FRC) for grants awarded to F.F., the FRC Rotary for an equipment grant awarded to the Institut du Fer à Moulin, the Swiss National Science Foundation (SNSF 31003A-135574, SPUM-33CM30-124089 and 33CM30-140332) and the Fondation Gianni Biaggi de Blasys for grants awarded to A.C., and the SNSF (31003A-125379) for grants awarded to E.W. We are particularly grateful to families and clinicians for access to their DNA samples. We also thank B. Barry, C. Walsh and collaborating clinicians for access to certain of their severe heterotopia patients. We thank W. van Ijcken for performing exome sequencing and R. Schot for excellent analysis of exome data of family 3489. We also thank W.B. Dobyns (Seattle Children's Research Institute) for critical review and classification of the MRI of the affected member of family 3489. We are grateful to D. Turner (University of Michigan) and N. Heintz (Rockefeller University) for reagents. We thank the imaging and animal house platforms at the Institut du Fer à Moulin and the Région Ile de France for support, as well as the animal facility and the Cellular Imaging Facility at the Département des Neurosiences Fondamentales. We thank J. Lemarchand, Y. Saillour, D. Derbala, M. Foglio, A. Boland, D. Zelenika, I. Gut, J.P. Hornung, D. Valloton, M. Niquille, C. Devenoges, N. Narboux-Neme, A. Cabrera, E. Bruel-Jungerman, R. Khalaf-Nazzal, X. Jaglin, T.D.H. Iuliano, M. Karababa, N. Magalhaes, M. Nosten-Bertrand, G. Grannec, A. Houllier and I. Moutkine for their contributions to this work. We are grateful to M. Groszer, J.-A. Girault, A. Houdusse, C. Moores, R. Bayliss, A. Fry, S. Cappello and M. Götz for discussions. The group of F.F. is affiliated with the Ecole des Neurosciences de Paris (ENP) and the Bio-Psy laboratory of excellence. The research leading to a part of these results received funding from the European Union Seventh Framework Programme FP7/2007–2013 under the project DESIRE (grant agreement no. 602531), la Fondation pour la Recherche Médicale (FRM, J Chelly–Equipe FRM 2013: DEQ2000326477) la Fondation Jacques Espinasse & Danièle (JED)-Belgique and the Spanish Ministry of Economy and Competitiveness grant (BFU2012-33473) awarded to V.B.

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Author notes

  1. Michel Kielar, Françoise Phan Dinh Tuy, Sara Bizzotto and Cécile Lebrand: These authors contributed equally to the work.

  2. Alexandre Croquelois and Fiona Francis: These authors jointly directed this work.

Authors and Affiliations

  1. Department of Clinical Neuroscience, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland

    Michel Kielar & Alexandre Croquelois

  2. Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland

    Michel Kielar, Cécile Lebrand, Egbert Welker & Alexandre Croquelois

  3. Inserm UMR-S 839, F75005, Paris, France

    Françoise Phan Dinh Tuy, Sara Bizzotto, Katia Boutourlinsky, Richard Belvindrah & Fiona Francis

  4. Sorbonne Université, Université Pierre et Marie Curie, Paris, France

    Françoise Phan Dinh Tuy, Sara Bizzotto, Katia Boutourlinsky, Dominique Boucher, Richard Belvindrah & Fiona Francis

  5. Institut du Fer à Moulin, Paris, France

    Françoise Phan Dinh Tuy, Sara Bizzotto, Katia Boutourlinsky, Richard Belvindrah & Fiona Francis

  6. Instituto de Neurociencias, Consejo Superior de Investigaciones Cientificas and Universidad Miguel Hernández, Alicante, Spain

    Camino de Juan Romero & Victor Borrell

  7. Inserm U1016, Université René Descartes, Institut Cochin, Paris, France

    Karine Poirier & Jamel Chelly

  8. Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands

    Renske Oegema & Grazia Maria Mancini

  9. Hopital Necker Enfants Malades, Pediatric Neurology, Assistance Publique Hôpitaux de Paris, Université Paris Descartes, Paris, France

    Nadia Bahi-Buisson

  10. Commissariat à l'Energie Atomique/Direction des Sciences du Vivant/Institut de Génomique, Centre National de Génotypage, 91057 Evry, France.,

    Robert Olaso & Jean-François Deleuze

  11. Service de Neuropédiatrie, Centre Hospitalier Universitaire Amiens-Nord, Amiens, France

    Anne-Gaëlle Le Moing & Patrick Berquin

  12. Laboratoire de Biologie du Développement, CNRS UMR 7622, Paris, France

    Dominique Boucher

  13. Plateforme post-génomique de la Pitié-Salpêtrière, Faculty of Medicine, Paris, France

    Wassila Carpentier

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  1. Michel Kielar
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Contributions

M.K. and F.P.D.T. carried out HeCo phenotyping and genotyping projects. F.P.D.T. characterized Eml1 at the genomic, cDNA and protein levels. F.P.D.T. and S.B. performed Vero, N2A, progenitor and neuronal cultures and analysis of EML1 and Eml1 (wild type and mutant) in vitro and mouse in situ hybridization studies, aided by K.B. S.B. performed rescue and shRNA in utero electroporations and analyses with help from R.B. M.K. performed the time lapse movies, pictures and reconstructed the movies. C.L. corrected the movie reconstruction and analyzed the films. C.D.J.R. and V.B. performed ferret in situ hybridizations and in utero transplantation analyses. K.P., R. Oegema, G.M.M., N.B.-B., A.G.L.M., P.B. and J.C. screened and characterized patients. K.P. and N.B.-B. followed and screened a patient DNA panel and controls. R. Oegema and G.M.M. performed exome sequencing and mutation confirmation. R. Olaso and J.-F.D. performed transcriptome experiments, genotyping data analysis and database submissions. D.B. aided with microtubule experiments. W.C. performed the second-round mouse genotyping experiment. E.W., A.C. and F.F. directed the study, analyzed the data and wrote the manuscript, greatly helped by M.K., F.P.D.T. and S.B.

Corresponding author

Correspondence to Fiona Francis.

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Kielar, M., Tuy, F., Bizzotto, S. et al. Mutations in Eml1 lead to ectopic progenitors and neuronal heterotopia in mouse and human. Nat Neurosci 17, 923–933 (2014). https://doi.org/10.1038/nn.3729

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