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Pax6 controls centriole maturation in cortical progenitors through Odf2

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Abstract

Cortical glutamatergic neurons are generated by radial glial cells (RGCs), specified by the expression of transcription factor (TF) Pax6, in the germinative zones of the dorsal telencephalon. Here, we demonstrate that Pax6 regulates the structural assembly of the interphase centrosomes. In the cortex of the Pax6-deficient Small eye (Sey/Sey) mutant, we find a defect of the appendages of the mother centrioles, indicating incomplete centrosome maturation. Consequently, RGCs fail to generate primary cilia, and instead of staying in the germinative zone for renewal, RGCs detach from the ventricular surface thus affecting the interkinetic nuclear migration and they exit prematurely from mitosis. Mechanistically, we show that TF Pax6 directly regulates the activity of the Odf2 gene encoding for the appendage-specific protein Odf2 with a role for the assembly of mother centriole. Our findings demonstrate a molecular mechanism that explains important characteristics of the centrosome disassembly and malfunctioning in developing cortex lacking Pax6.

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References

  1. Caviness VS Jr, Takahashi T (1995) Proliferative events in the cerebral ventricular zone. Brain Dev 17(3):159–163

    Article  PubMed  Google Scholar 

  2. Caviness VS Jr, Takahashi T, Nowakowski RS (1995) Numbers, time and neocortical neuronogenesis: a general developmental and evolutionary model. Trends Neurosci 18(9):379–383

    Article  CAS  PubMed  Google Scholar 

  3. Gotz M, Huttner WB (2005) The cell biology of neurogenesis. Nat Rev Mol Cell Biol 6(10):777–788. doi:10.1038/nrm1739

    Article  PubMed  Google Scholar 

  4. Kriegstein A, Noctor S, Martinez-Cerdeno V (2006) Patterns of neural stem and progenitor cell division may underlie evolutionary cortical expansion. Nat Rev Neurosci 7(11):883–890. doi:10.1038/nrn2008

    Article  CAS  PubMed  Google Scholar 

  5. Malatesta P, Hartfuss E, Gotz M (2000) Isolation of radial glial cells by fluorescent-activated cell sorting reveals a neuronal lineage. Development 127(24):5253–5263

    CAS  PubMed  Google Scholar 

  6. Miyata T (2007) Asymmetric cell division during brain morphogenesis. Prog Mol Subcell Biol 45:121–142

    Article  CAS  PubMed  Google Scholar 

  7. Noctor SC, Flint AC, Weissman TA, Dammerman RS, Kriegstein AR (2001) Neurons derived from radial glial cells establish radial units in neocortex. Nature 409(6821):714–720. doi:10.1038/35055553

    Article  CAS  PubMed  Google Scholar 

  8. Rakic P (2009) Evolution of the neocortex: a perspective from developmental biology. Nat Rev Neurosci 10(10):724–735. doi:10.1038/nrn2719

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. McConnell SK, Kaznowski CE (1991) Cell cycle dependence of laminar determination in developing neocortex. Science 254(5029):282–285

    Article  CAS  PubMed  Google Scholar 

  10. Angevine JB Jr, Sidman RL (1961) Autoradiographic study of cell migration during histogenesis of cerebral cortex in the mouse. Nature 192:766–768

    Article  PubMed  Google Scholar 

  11. Rakic P, Stensas LJ, Sayre E, Sidman RL (1974) Computer-aided three-dimensional reconstruction and quantitative analysis of cells from serial electron microscopic montages of foetal monkey brain. Nature 250(461):31–34

    Article  CAS  PubMed  Google Scholar 

  12. Haubensak W, Attardo A, Denk W, Huttner WB (2004) Neurons arise in the basal neuroepithelium of the early mammalian telencephalon: a major site of neurogenesis. Proc Natl Acad Sci USA 101(9):3196–3201. doi:10.1073/pnas.0308600100

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Lukaszewicz A, Savatier P, Cortay V, Giroud P, Huissoud C, Berland M, Kennedy H, Dehay C (2005) G1 phase regulation, area-specific cell cycle control, and cytoarchitectonics in the primate cortex. Neuron 47(3):353–364. doi:10.1016/j.neuron.2005.06.032

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Noctor SC, Martinez-Cerdeno V, Ivic L, Kriegstein AR (2004) Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases. Nat Neurosci 7(2):136–144. doi:10.1038/nn1172

    Article  CAS  PubMed  Google Scholar 

  15. Bishop KM, Goudreau G, O’Leary DD (2000) Regulation of area identity in the mammalian neocortex by Emx2 and Pax6. Science 288(5464):344–349

    Article  CAS  PubMed  Google Scholar 

  16. Georgala PA, Carr CB, Price DJ (2011) The role of Pax6 in forebrain development. Dev Neurobiol 71(8):690–709. doi:10.1002/dneu.20895

    Article  CAS  PubMed  Google Scholar 

  17. Hevner RF, Shi L, Justice N, Hsueh Y, Sheng M, Smiga S, Bulfone A, Goffinet AM, Campagnoni AT, Rubenstein JL (2001) Tbr1 regulates differentiation of the preplate and layer 6. Neuron 29(2):353–366

    Article  CAS  PubMed  Google Scholar 

  18. Tuoc TC, Radyushkin K, Tonchev AB, Pinon MC, Ashery-Padan R, Molnar Z, Davidoff MS, Stoykova A (2009) Selective cortical layering abnormalities and behavioral deficits in cortex-specific Pax6 knock-out mice. J Neurosci 29(26):8335–8349. doi:10.1523/JNEUROSCI.5669-08.2009

    Article  CAS  PubMed  Google Scholar 

  19. Zembrzycki A, Chou SJ, Ashery-Padan R, Stoykova A, O’Leary DD (2013) Sensory cortex limits cortical maps and drives top-down plasticity in thalamocortical circuits. Nat Neurosci 16(8):1060–1067. doi:10.1038/nn.3454

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Hill RE, Favor J, Hogan BL, Ton CC, Saunders GF, Hanson IM, Prosser J, Jordan T, Hastie ND, van Heyningen V (1991) Mouse small eye results from mutations in a paired-like homeobox-containing gene. Nature 354(6354):522–525. doi:10.1038/354522a0

    Article  CAS  PubMed  Google Scholar 

  21. Heins N, Malatesta P, Cecconi F, Nakafuku M, Tucker KL, Hack MA, Chapouton P, Barde YA, Gotz M (2002) Glial cells generate neurons: the role of the transcription factor Pax6. Nat Neurosci 5(4):308–315. doi:10.1038/nn828

    Article  CAS  PubMed  Google Scholar 

  22. Caric D, Gooday D, Hill RE, McConnell SK, Price DJ (1997) Determination of the migratory capacity of embryonic cortical cells lacking the transcription factor Pax-6. Development 124(24):5087–5096

    CAS  PubMed  Google Scholar 

  23. Georgala PA, Manuel M, Price DJ (2011) The generation of superficial cortical layers is regulated by levels of the transcription factor Pax6. Cereb Cortex 21(1):81–94. doi:10.1093/cercor/bhq061

    Article  PubMed Central  PubMed  Google Scholar 

  24. Quinn JC, Molinek M, Martynoga BS, Zaki PA, Faedo A, Bulfone A, Hevner RF, West JD, Price DJ (2007) Pax6 controls cerebral cortical cell number by regulating exit from the cell cycle and specifies cortical cell identity by a cell autonomous mechanism. Dev Biol 302(1):50–65. doi:10.1016/j.ydbio.2006.08.035

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Sansom SN, Livesey FJ (2009) Gradients in the brain: the control of the development of form and function in the cerebral cortex. Cold Spring Harb Perspect Biol 1(2):a002519. doi:10.1101/cshperspect.a002519

    Article  PubMed Central  PubMed  Google Scholar 

  26. Schmahl W, Knoedlseder M, Favor J, Davidson D (1993) Defects of neuronal migration and the pathogenesis of cortical malformations are associated with Small eye (Sey) in the mouse, a point mutation at the Pax-6-locus. Acta Neuropathol 86(2):126–135

    Article  CAS  PubMed  Google Scholar 

  27. Stoykova A, Fritsch R, Walther C, Gruss P (1996) Forebrain patterning defects in Small eye mutant mice. Development 122(11):3453–3465

    CAS  PubMed  Google Scholar 

  28. Tarabykin V, Stoykova A, Usman N, Gruss P (2001) Cortical upper layer neurons derive from the subventricular zone as indicated by Svet1 gene expression. Development 128(11):1983–1993

    CAS  PubMed  Google Scholar 

  29. Gotz M, Stoykova A, Gruss P (1998) Pax6 controls radial glia differentiation in the cerebral cortex. Neuron 21(5):1031–1044

    Article  CAS  PubMed  Google Scholar 

  30. Asami M, Pilz GA, Ninkovic J, Godinho L, Schroeder T, Huttner WB, Gotz M (2011) The role of Pax6 in regulating the orientation and mode of cell division of progenitors in the mouse cerebral cortex. Development 138(23):5067–5078. doi:10.1242/dev.074591

    Article  CAS  PubMed  Google Scholar 

  31. Tamai H, Shinohara H, Miyata T, Saito K, Nishizawa Y, Nomura T, Osumi N (2007) Pax6 transcription factor is required for the interkinetic nuclear movement of neuroepithelial cells. Genes Cells 12(9):983–996. doi:10.1111/j.1365-2443.2007.01113.x

    Article  CAS  PubMed  Google Scholar 

  32. Tuoc TC, Stoykova A (2008) Er81 is a downstream target of Pax6 in cortical progenitors. BMC Dev Biol 8:23. doi:10.1186/1471-213X-8-23

    Article  PubMed Central  PubMed  Google Scholar 

  33. Kosodo Y (2012) Interkinetic nuclear migration: beyond a hallmark of neurogenesis. Cell Mol Life Sci 69(16):2727–2738. doi:10.1007/s00018-012-0952-2

    Article  CAS  PubMed  Google Scholar 

  34. Bornens M (2002) Centrosome composition and microtubule anchoring mechanisms. Curr Opin Cell Biol 14(1):25–34

    Article  CAS  PubMed  Google Scholar 

  35. Higginbotham HR, Gleeson JG (2007) The centrosome in neuronal development. Trends Neurosci 30(6):276–283. doi:10.1016/j.tins.2007.04.001

    Article  CAS  PubMed  Google Scholar 

  36. Tsou MF, Stearns T (2006) Mechanism limiting centrosome duplication to once per cell cycle. Nature 442(7105):947–951. doi:10.1038/nature04985

    Article  CAS  PubMed  Google Scholar 

  37. Bouckson-Castaing V, Moudjou M, Ferguson DJ, Mucklow S, Belkaid Y, Milon G, Crocker PR (1996) Molecular characterisation of ninein, a new coiled-coil protein of the centrosome. J Cell Sci 109(Pt 1):179–190

    CAS  PubMed  Google Scholar 

  38. Lange BM, Gull K (1995) A molecular marker for centriole maturation in the mammalian cell cycle. J Cell Biol 130(4):919–927

    Article  CAS  PubMed  Google Scholar 

  39. Nakagawa Y, Yamane Y, Okanoue T, Tsukita S, Tsukita S (2001) Outer dense fiber 2 is a widespread centrosome scaffold component preferentially associated with mother centrioles: its identification from isolated centrosomes. Mol Biol Cell 12(6):1687–1697

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Ou YY, Mack GJ, Zhang M, Rattner JB (2002) CEP110 and ninein are located in a specific domain of the centrosome associated with centrosome maturation. J Cell Sci 115(Pt 9):1825–1835

    CAS  PubMed  Google Scholar 

  41. Piel M, Meyer P, Khodjakov A, Rieder CL, Bornens M (2000) The respective contributions of the mother and daughter centrioles to centrosome activity and behavior in vertebrate cells. J Cell Biol 149(2):317–330

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Wang X, Tsai JW, Imai JH, Lian WN, Vallee RB, Shi SH (2009) Asymmetric centrosome inheritance maintains neural progenitors in the neocortex. Nature 461(7266):947–955. doi:10.1038/nature08435

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Hoyer-Fender S (2010) Centriole maturation and transformation to basal body. Semin Cell Dev Biol 21(2):142–147. doi:10.1016/j.semcdb.2009.07.002

    Article  PubMed  Google Scholar 

  44. Kobayashi T, Dynlacht BD (2011) Regulating the transition from centriole to basal body. J Cell Biol 193(3):435–444. doi:10.1083/jcb.201101005

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Willaredt MA, Hasenpusch-Theil K, Gardner HA, Kitanovic I, Hirschfeld-Warneken VC, Gojak CP, Gorgas K, Bradford CL, Spatz J, Wolfl S, Theil T, Tucker KL (2008) A crucial role for primary cilia in cortical morphogenesis. J Neurosci 28(48):12887–12900. doi:10.1523/JNEUROSCI.2084-08.2008

    Article  CAS  PubMed  Google Scholar 

  46. Willaredt MA, Tasouri E, Tucker KL (2012) Primary cilia and forebrain development. Mech Dev. doi:10.1016/j.mod.2012.10.003

    PubMed  Google Scholar 

  47. Ishikawa H, Kubo A, Tsukita S (2005) Odf2-deficient mother centrioles lack distal/subdistal appendages and the ability to generate primary cilia. Nat Cell Biol 7(5):517–524. doi:10.1038/ncb1251

    Article  CAS  PubMed  Google Scholar 

  48. Tong CK, Han YG, Shah JK, Obernier K, Guinto CD, Alvarez-Buylla A (2014) Primary cilia are required in a unique subpopulation of neural progenitors. Proc Natl Acad Sci USA. doi:10.1073/pnas.1321425111

    Google Scholar 

  49. Imai JH, Wang X, Shi SH (2010) Kaede-centrin1 labeling of mother and daughter centrosomes in mammalian neocortical neural progenitors. Curr Protoc Stem Cell Biol 5:5A. doi:10.1002/9780470151808.sc05a05s15

    Google Scholar 

  50. Ashery-Padan R, Marquardt T, Zhou X, Gruss P (2000) Pax6 activity in the lens primordium is required for lens formation and for correct placement of a single retina in the eye. Genes Dev 14(21):2701–2711

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Gorski JA, Talley T, Qiu M, Puelles L, Rubenstein JL, Jones KR (2002) Cortical excitatory neurons and glia, but not GABAergic neurons, are produced in the Emx1-expressing lineage. J Neurosci 22(15):6309–6314. doi:10.1016/b0-12-227210-2/00147-3

  52. Cai L, Hayes NL, Nowakowski RS (1997) Local homogeneity of cell cycle length in developing mouse cortex. J Neurosci 17(6):2079–2087

    CAS  PubMed  Google Scholar 

  53. Walther C, Gruss P (1991) Pax-6, a murine paired box gene, is expressed in the developing CNS. Development 113(4):1435–1449

    CAS  PubMed  Google Scholar 

  54. Ibi M, Zou P, Inoko A, Shiromizu T, Matsuyama M, Hayashi Y, Enomoto M, Mori D, Hirotsune S, Kiyono T, Tsukita S, Goto H, Inagaki M (2011) Trichoplein controls microtubule anchoring at the centrosome by binding to Odf2 and ninein. J Cell Sci 124(Pt 6):857–864. doi:10.1242/jcs.075705

    Article  CAS  PubMed  Google Scholar 

  55. Pletz N, Medack A, Riess EM, Yang K, Kazerouni ZB, Huber D (1833) Hoyer-Fender S (2013) Transcriptional activation of Odf2/Cenexin by cell cycle arrest and the stress activated signaling pathway (JNK pathway). Biochim Biophys Acta 6:1338–1346. doi:10.1016/j.bbamcr.2013.02.023

    Google Scholar 

  56. Baumer N, Marquardt T, Stoykova A, Spieler D, Treichel D, Ashery-Padan R, Gruss P (2003) Retinal pigmented epithelium determination requires the redundant activities of Pax2 and Pax6. Development 130(13):2903–2915

    Article  PubMed  Google Scholar 

  57. Stoykova A, Treichel D, Hallonet M, Gruss P (2000) Pax6 modulates the dorsoventral patterning of the mammalian telencephalon. J Neurosci 20(21):8042–8050

    CAS  PubMed  Google Scholar 

  58. Yun K, Potter S, Rubenstein JL (2001) Gsh2 and Pax6 play complementary roles in dorsoventral patterning of the mammalian telencephalon. Development 128(2):193–205

    CAS  PubMed  Google Scholar 

  59. Toresson H, Potter SS, Campbell K (2000) Genetic control of dorsal-ventral identity in the telencephalon: opposing roles for Pax6 and Gsh2. Development 127(20):4361–4371

    CAS  PubMed  Google Scholar 

  60. Warren N, Caric D, Pratt T, Clausen JA, Asavaritikrai P, Mason JO, Hill RE, Price DJ (1999) The transcription factor, Pax6, is required for cell proliferation and differentiation in the developing cerebral cortex. Cereb Cortex 9(6):627–635

    Article  CAS  PubMed  Google Scholar 

  61. Kroll TT, O’Leary DD (2005) Ventralized dorsal telencephalic progenitors in Pax6 mutant mice generate GABA interneurons of a lateral ganglionic eminence fate. Proc Natl Acad Sci USA 102(20):7374–7379. doi:10.1073/pnas.0500819102

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  62. Estivill-Torrus G, Pearson H, van Heyningen V, Price DJ, Rashbass P (2002) Pax6 is required to regulate the cell cycle and the rate of progression from symmetrical to asymmetrical division in mammalian cortical progenitors. Development 129(2):455–466

    CAS  PubMed  Google Scholar 

  63. Schuurmans C, Armant O, Nieto M, Stenman JM, Britz O, Klenin N, Brown C, Langevin LM, Seibt J, Tang H, Cunningham JM, Dyck R, Walsh C, Campbell K, Polleux F, Guillemot F (2004) Sequential phases of cortical specification involve Neurogenin-dependent and -independent pathways. EMBO J 23(14):2892–2902. doi:10.1038/sj.emboj.7600278

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  64. Messier PE, Auclair C (1973) Inhibition of nuclear migration in the absence of microtubules in the chick embryo. J Embryol Exp Morphol 30(3):661–671

    CAS  PubMed  Google Scholar 

  65. Osumi N, Shinohara H, Numayama-Tsuruta K, Maekawa M (2008) Concise review: Pax6 transcription factor contributes to both embryonic and adult neurogenesis as a multifunctional regulator. Stem Cells 26(7):1663–1672. doi:10.1634/stemcells.2007-0884

    Article  CAS  PubMed  Google Scholar 

  66. Azimzadeh J, Bornens M (2007) Structure and duplication of the centrosome. J Cell Sci 120(Pt 13):2139–2142. doi:10.1242/jcs.005231

    Article  CAS  PubMed  Google Scholar 

  67. Bornens M (2012) The centrosome in cells and organisms. Science 335(6067):422–426. doi:10.1126/science.1209037

    Article  CAS  PubMed  Google Scholar 

  68. Meraldi P, Nigg EA (2002) The centrosome cycle. FEBS Lett 521(1–3):9–13

    Article  CAS  PubMed  Google Scholar 

  69. Shinohara H, Sakayori N, Takahashi M, Osumi N (2013) Ninein is essential for the maintenance of the cortical progenitor character by anchoring the centrosome to microtubules. Biol Open 2(7):739–749. doi:10.1242/bio.20135231

    Article  PubMed Central  PubMed  Google Scholar 

  70. Corbit KC, Shyer AE, Dowdle WE, Gaulden J, Singla V, Chen MH, Chuang PT, Reiter JF (2008) Kif3a constrains beta-catenin-dependent Wnt signalling through dual ciliary and non-ciliary mechanisms. Nat Cell Biol 10(1):70–76. doi:10.1038/ncb1670

    Article  CAS  PubMed  Google Scholar 

  71. Gerdes JM, Liu Y, Zaghloul NA, Leitch CC, Lawson SS, Kato M, Beachy PA, Beales PL, DeMartino GN, Fisher S, Badano JL, Katsanis N (2007) Disruption of the basal body compromises proteasomal function and perturbs intracellular Wnt response. Nat Genet 39(11):1350–1360. doi:10.1038/ng.2007.12

    Article  CAS  PubMed  Google Scholar 

  72. Muzio L, DiBenedetto B, Stoykova A, Boncinelli E, Gruss P, Mallamaci A (2002) Emx2 and Pax6 control regionalization of the pre-neuronogenic cortical primordium. Cereb Cortex 12(2):129–139

    Article  PubMed  Google Scholar 

  73. Epstein JA, Glaser T, Cai J, Jepeal L, Walton DS, Maas RL (1994) Two independent and interactive DNA-binding subdomains of the Pax6 paired domain are regulated by alternative splicing. Genes Dev 8(17):2022–2034

    Article  CAS  PubMed  Google Scholar 

  74. Muhlfriedel S, Kirsch F, Gruss P, Chowdhury K, Stoykova A (2007) Novel genes differentially expressed in cortical regions during late neurogenesis. Eur J Neurosci 26(1):33–50. doi:10.1111/j.1460-9568.2007.05639.x

    Article  PubMed  Google Scholar 

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Acknowledgments

The authors thank Prof. Dr. med Nicolai Miosge for technical and knowledge support regarding electron microscopy. Thanks are also due to Silke Schlott and Martina Daniel for excellent technical assistance. We thank T. Schweizer for proofreading. Marco A. Tylkowski was funded through Cluster of Excellence and DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain.

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Authors and Affiliations

  1. Research Group of Molecular Developmental Neurobiology, Department Molecular Cell Biology, Max-Planck Institute for Biophysical Chemistry, Am Faßberg 11, 37077, Göttingen, Germany

    Marco A. Tylkowski & Anastassia Stoykova

  2. Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), 37075, Göttingen, Germany

    Marco A. Tylkowski & Anastassia Stoykova

  3. Johann-Friedrich-Blumenbach-Institute of Zoology and Anthropology, Developmental Biology, GZMB, Ernst-Caspari-Haus, Georg-August-Universität Göttingen, Justus-von-Liebig-Weg 11, Göttingen, Germany

    Kefei Yang & Sigrid Hoyer-Fender

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  1. Marco A. Tylkowski
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Tylkowski, M.A., Yang, K., Hoyer-Fender, S. et al. Pax6 controls centriole maturation in cortical progenitors through Odf2 . Cell. Mol. Life Sci. 72, 1795–1809 (2015). https://doi.org/10.1007/s00018-014-1766-1

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