Advertisement

The Role of the Transcription Factor Pax6 in Brain Development and Evolution: Evidence and Hypothesis

  • Noriko Osumi
  • Takako Kikkawa

Abstract

During mammalian corticogenesis, the dorsal telencephalon is patterned through secreted molecules and transcription factors. Expression of the transcription factor Pax6 demarcates the dorsal telencephalon, thereby patterning the future cortical primordium. Pax6 is also crucial in neurogenesis in the developing cortex through its role in balancing proliferation and differentiation of neural progenitor cells (NPCs). In this chapter, we address the role of Pax6 and its downstream molecules in cortical development and evolution. We also note the possible involvement of Pax6 in the onset of neurodevelopmental diseases.

Keywords

Ventricular Zone Radial Glia PAX6 Gene Pax6 Expression Radial Glia Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

We thank Dr. Yuji Tsunekawa and Mr. Nobuyuki Sakayori for kindly providing their immunohistochemical data. This work was supported by a grant-in-aid for Scientific Research on Priority Areas “Molecular Brain Science” and “Corticogenesis” (to N. O.) from MEXT Japan. T.K. was supported by a Research Fellowship of the Japan Society for the Promotion of Science for Young Scientists.

References

  1. Abrahams BS, Geschwind DH (2008) Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet 9(5):341–355. doi: 10.1038/nrg2346 PubMedGoogle Scholar
  2. Agca C, Elhajj MC, Klein WH, Venuti JM (2011) Neurosensory and neuromuscular organization in tube feet of the sea urchin Strongylocentrotus purpuratus. J Comp Neurol 519(17):3566–3579. doi: 10.1002/cne.22724 PubMedGoogle Scholar
  3. Amaral DG, Schumann CM, Nordahl CW (2008) Neuroanatomy of autism. Trends Neurosci 31(3):137–145. doi: 10.1016/j.tins.2007.12.005 PubMedGoogle Scholar
  4. Andrews GL, Mastick GS (2003) R-cadherin is a Pax6-regulated, growth-promoting cue for pioneer axons. J Neurosci 23(30):9873–9880PubMedGoogle Scholar
  5. Arai Y, Funatsu N, Numayama-Tsuruta K, Nomura T, Nakamura S, Osumi N (2005) Role of Fabp7, a downstream gene of Pax6, in the maintenance of neuroepithelial cells during early embryonic development of the rat cortex. J Neurosci 25(42):9752–9761. doi: 10.1523/JNEUROSCI.2512-05.2005 PubMedGoogle Scholar
  6. 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 PubMedGoogle Scholar
  7. Ashley CT Jr, Wilkinson KD, Reines D, Warren ST (1993) FMR1 protein: conserved RNP family domains and selective RNA binding. Science 262(5133):563–566PubMedGoogle Scholar
  8. Bagni C, Greenough WT (2005) From mRNP trafficking to spine dysmorphogenesis: the roots of fragile X syndrome. Nat Rev Neurosci 6(5):376–387. doi: 10.1038/nrn1667 PubMedGoogle Scholar
  9. Bassell GJ, Warren ST (2008) Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function. Neuron 60(2):201–214. doi: 10.1016/j.neuron.2008.10.004 PubMedGoogle Scholar
  10. Bender CM, Gonzalgo ML, Gonzales FA, Nguyen CT, Robertson KD, Jones PA (1999) Roles of cell division and gene transcription in the methylation of CpG islands. Mol Cell Biol 19(10):6690–6698PubMedGoogle Scholar
  11. Bentley CA, Zidehsarai MP, Grindley JC, Parlow AF, Barth-Hall S, Roberts VJ (1999) Pax6 is implicated in murine pituitary endocrine function. Endocrine 10(2):171–177. doi: 10.1385/ENDO:10:2:171 PubMedGoogle Scholar
  12. Bhakar AL, Dolen G, Bear MF (2012) The pathophysiology of fragile X (and what it teaches us about synapses). Annu Rev Neurosci 35:417–443. doi: 10.1146/annurev-neuro-060909-153138 PubMedGoogle Scholar
  13. Bishop KM, Rubenstein JL, O’Leary DD (2002) Distinct actions of Emx1, Emx2, and Pax6 in regulating the specification of areas in the developing neocortex. J Neurosci 22(17):7627–7638PubMedGoogle Scholar
  14. Buffo A, Vosko MR, Erturk D, Hamann GF, Jucker M, Rowitch D, Gotz M (2005) Expression pattern of the transcription factor Olig2 in response to brain injuries: implications for neuronal repair. Proc Natl Acad Sci USA 102(50):18183–18188. doi: 10.1073/pnas.0506535102 PubMedGoogle Scholar
  15. Chandra S, Fornai F, Kwon HB, Yazdani U, Atasoy D, Liu X, Hammer RE, Battaglia G, German DC, Castillo PE, Sudhof TC (2004) Double-knockout mice for alpha- and beta-synucleins: effect on synaptic functions. Proc Natl Acad Sci USA 101(41):14966–14971. doi: 10.1073/pnas.0406283101 PubMedGoogle Scholar
  16. Costa MR, Kessaris N, Richardson WD, Gotz M, Hedin-Pereira C (2007) The marginal zone/layer I as a novel niche for neurogenesis and gliogenesis in developing cerebral cortex. J Neurosci 27(42):11376–11388. doi: 10.1523/JNEUROSCI.2418-07.2007 PubMedGoogle Scholar
  17. Coutinho P, Pavlou S, Bhatia S, Chalmers KJ, Kleinjan DA, van Heyningen V (2011) Discovery and assessment of conserved Pax6 target genes and enhancers. Genome Res 21(8):1349–1359. doi: 10.1101/gr.124115.111 PubMedGoogle Scholar
  18. Cross SH, Clark VH, Bird AP (1999) Isolation of CpG islands from large genomic clones. Nucleic Acids Res 27(10):2099–2107PubMedGoogle Scholar
  19. Czerny T, Busslinger M (1995) DNA-binding and transactivation properties of Pax-6: three amino acids in the paired domain are responsible for the different sequence recognition of Pax-6 and BSAP (Pax-5). Mol Cell Biol 15(5):2858–2871PubMedGoogle Scholar
  20. Davis LK, Meyer KJ, Rudd DS, Librant AL, Epping EA, Sheffield VC, Wassink TH (2008) Pax6 3' deletion results in aniridia, autism and mental retardation. Hum Genet 123(4):371–378. doi: 10.1007/s00439-008-0484-x PubMedGoogle Scholar
  21. Dimanlig PV, Faber SC, Auerbach W, Makarenkova HP, Lang RA (2001) The upstream ectoderm enhancer in Pax6 has an important role in lens induction. Development 128(22):4415–4424PubMedGoogle Scholar
  22. Duparc RH, Boutemmine D, Champagne MP, Tetreault N, Bernier G (2006) Pax6 is required for delta-catenin/neurojugin expression during retinal, cerebellar and cortical development in mice. Dev Biol 300(2):647–655. doi: 10.1016/j.ydbio.2006.07.045 PubMedGoogle Scholar
  23. Duvall JA, Lu A, Cantor RM, Todd RD, Constantino JN, Geschwind DH (2007) A quantitative trait locus analysis of social responsiveness in multiplex autism families. Am J Psychiatry 164(4):656–662. doi: 10.1176/appi.ajp.164.4.656 PubMedGoogle Scholar
  24. Englund C, Fink A, Lau C, Pham D, Daza RA, Bulfone A, Kowalczyk T, Hevner RF (2005) Pax6, Tbr2, and Tbr1 are expressed sequentially by radial glia, intermediate progenitor cells, and postmitotic neurons in developing neocortex. J Neurosci 25(1):247–251. doi: 10.1523/JNEUROSCI.2899-04.2005 PubMedGoogle Scholar
  25. Erclik T, Hartenstein V, McInnes RR, Lipshitz HD (2009) Eye evolution at high resolution: the neuron as a unit of homology. Dev Biol 332(1):70–79. doi: 10.1016/j.ydbio.2009.05.565 PubMedGoogle Scholar
  26. Ericson J, Rashbass P, Schedl A, Brenner-Morton S, Kawakami A, van Heyningen V, Jessell TM, Briscoe J (1997) Pax6 controls progenitor cell identity and neuronal fate in response to graded Shh signaling. Cell 90(1):169–180PubMedGoogle Scholar
  27. 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):455–466PubMedGoogle Scholar
  28. Fietz SA, Kelava I, Vogt J, Wilsch-Brauninger M, Stenzel D, Fish JL, Corbeil D, Riehn A, Distler W, Nitsch R, Huttner WB (2010) OSVZ progenitors of human and ferret neocortex are epithelial-like and expand by integrin signaling. Nat Neurosci 13(6):690–699. doi: 10.1038/nn.2553 PubMedGoogle Scholar
  29. Fietz SA, Lachmann R, Brandl H, Kircher M, Samusik N, Schroder R, Lakshmanaperumal N, Henry I, Vogt J, Riehn A, Distler W, Nitsch R, Enard W, Paabo S, Huttner WB (2012) Transcriptomes of germinal zones of human and mouse fetal neocortex suggest a role of extracellular matrix in progenitor self-renewal. Proc Natl Acad Sci USA 109(29):11836–11841. doi: 10.1073/pnas.1209647109 PubMedGoogle Scholar
  30. Fish JL, Dehay C, Kennedy H, Huttner WB (2008) Making bigger brains-the evolution of neural-progenitor-cell division. J Cell Sci 121(Pt 17):2783–2793. doi: 10.1242/jcs.023465 PubMedGoogle Scholar
  31. Fisher SE, Scharff C (2009) FOXP2 as a molecular window into speech and language. Trends genet 25(4):166–177. doi: 10.1016/j.tig.2009.03.002 PubMedGoogle Scholar
  32. Fukuda T, Kawano H, Osumi N, Eto K, Kawamura K (2000) Histogenesis of the cerebral cortex in rat fetuses with a mutation in the Pax-6 gene. Brain Res Dev Brain Res 120(1):65–75PubMedGoogle Scholar
  33. Fukuzaki U, Osumi N (2007) The search for downstream target genes of Pax6 using microassay analysis. Future medical engineering based on bionanotechnology. Imperial College Press, LondonGoogle Scholar
  34. Gehring WJ (1996) The master control gene for morphogenesis and evolution of the eye. Genes cells 1(1):11–15PubMedGoogle Scholar
  35. Gehring WJ (2002) The genetic control of eye development and its implications for the evolution of the various eye-types. Int J Dev Biol 46(1):65–73PubMedGoogle Scholar
  36. Gomez-Lopez S, Wiskow O, Favaro R, Nicolis SK, Price DJ, Pollard SM, Smith A (2011) Sox2 and Pax6 maintain the proliferative and developmental potential of gliogenic neural stem cells In vitro. Glia 59(11):1588–1599. doi: 10.1002/glia.21201 PubMedGoogle Scholar
  37. Gosmain Y, Cheyssac C, Heddad Masson M, Dibner C, Philippe J (2011) Glucagon gene expression in the endocrine pancreas: the role of the transcription factor Pax6 in alpha-cell differentiation, glucagon biosynthesis and secretion. Diabetes Obes Metab 13(Suppl 1):31–38. doi: 10.1111/j.1463-1326.2011.01445.x PubMedGoogle Scholar
  38. Gotz M, Stoykova A, Gruss P (1998) Pax6 controls radial glia differentiation in the cerebral cortex. Neuron 21(5):1031–1044. doi:S0896-6273(00)80621-2 [pii]PubMedGoogle Scholar
  39. Griveau A, Borello U, Causeret F, Tissir F, Boggetto N, Karaz S, Pierani A (2010) A novel role for Dbx1-derived Cajal-Retzius cells in early regionalization of the cerebral cortical neuroepithelium. PLoS Biol 8(7):e1000440. doi: 10.1371/journal.pbio.1000440 PubMedGoogle Scholar
  40. Haba H, Nomura T, Suto F, Osumi N (2009) Subtype-specific reduction of olfactory bulb interneurons in Pax6 heterozygous mutant mice. Neurosci Res 65(1):116–121. doi: 10.1016/j.neures.2009.05.011 PubMedGoogle Scholar
  41. Hack MA, Saghatelyan A, de Chevigny A, Pfeifer A, Ashery-Padan R, Lledo PM, Gotz M (2005) Neuronal fate determinants of adult olfactory bulb neurogenesis. Nat Neurosci 8(7):865–872. doi: 10.1038/nn1479 PubMedGoogle Scholar
  42. Halder G, Callaerts P, Gehring WJ (1995) New perspectives on eye evolution. Curr Opin Genet Dev 5(5):602–609PubMedGoogle Scholar
  43. Halfter W, Dong S, Yip YP, Willem M, Mayer U (2002) A critical function of the pial basement membrane in cortical histogenesis. J Neurosci 22(14):6029–6040. doi:20026580PubMedGoogle Scholar
  44. Hansen DV, Lui JH, Parker PR, Kriegstein AR (2010) Neurogenic radial glia in the outer subventricular zone of human neocortex. Nature 464(7288):554–561. doi: 10.1038/nature08845 PubMedGoogle Scholar
  45. Hanson I, Van Heyningen V (1995) Pax6: more than meets the eye. Trends genet 11(7):268–272PubMedGoogle Scholar
  46. Haubst N, Georges-Labouesse E, De Arcangelis A, Mayer U, Gotz M (2006) Basement membrane attachment is dispensable for radial glial cell fate and for proliferation, but affects positioning of neuronal subtypes. Development 133(16):3245–3254. doi: 10.1242/dev.02486 PubMedGoogle Scholar
  47. 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 PubMedGoogle Scholar
  48. Hevner RF, Hodge RD, Daza RA, Englund C (2006) Transcription factors in glutamatergic neurogenesis: conserved programs in neocortex, cerebellum, and adult hippocampus. Neurosci Res 55(3):223–233. doi: 10.1016/j.neures.2006.03.004 PubMedGoogle Scholar
  49. 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 PubMedGoogle Scholar
  50. Hirata T, Nomura T, Takagi Y, Sato Y, Tomioka N, Fujisawa H, Osumi N (2002) Mosaic development of the olfactory cortex with Pax6-dependent and -independent components. Brain Res Dev Brain Res 136(1):17–26PubMedGoogle Scholar
  51. Inoue T, Nakamura S, Osumi N (2000) Fate mapping of the mouse prosencephalic neural plate. Dev Biol 219(2):373–383. doi: 10.1006/dbio.2000.9616 PubMedGoogle Scholar
  52. Kammandel B, Chowdhury K, Stoykova A, Aparicio S, Brenner S, Gruss P (1999) Distinct cis-essential modules direct the time-space pattern of the Pax6 gene activity. Dev Biol 205(1):79–97. doi: 10.1006/dbio.1998.9128 PubMedGoogle Scholar
  53. Kioussi C, O'Connell S, St-Onge L, Treier M, Gleiberman AS, Gruss P, Rosenfeld MG (1999) Pax6 is essential for establishing ventral-dorsal cell boundaries in pituitary gland development. Proc Natl Acad Sci USA 96(25):14378–14382PubMedGoogle Scholar
  54. Kleinjan DA, Seawright A, Childs AJ, van Heyningen V (2004) Conserved elements in Pax6 intron 7 involved in (auto)regulation and alternative transcription. Dev Biol 265(2):462–477PubMedGoogle Scholar
  55. Kleinjan DA, Bancewicz RM, Gautier P, Dahm R, Schonthaler HB, Damante G, Seawright A, Hever AM, Yeyati PL, van Heyningen V, Coutinho P (2008) Subfunctionalization of duplicated zebrafish pax6 genes by cis-regulatory divergence. PLoS Genet 4(2):e29. doi: 10.1371/journal.pgen.0040029 PubMedGoogle Scholar
  56. Kohwi M, Osumi N, Rubenstein JL, Alvarez-Buylla A (2005) Pax6 is required for making specific subpopulations of granule and periglomerular neurons in the olfactory bulb. J Neurosci 25(30):6997–7003. doi: 10.1523/JNEUROSCI.1435-05.2005 PubMedGoogle Scholar
  57. Kozmik Z (2005) Pax genes in eye development and evolution. Curr Opin Genet Dev 15(4):430–438. doi: 10.1016/j.gde.2005.05.001 PubMedGoogle Scholar
  58. LaMonica BE, Lui JH, Wang X, Kriegstein AR (2012) OSVZ progenitors in the human cortex: an updated perspective on neurodevelopmental disease. Curr Opin Neurobiol 22(5):747–753. doi: 10.1016/j.conb.2012.03.006 PubMedGoogle Scholar
  59. Loulier K, Lathia JD, Marthiens V, Relucio J, Mughal MR, Tang SC, Coksaygan T, Hall PE, Chigurupati S, Patton B, Colognato H, Rao MS, Mattson MP, Haydar TF, Ffrench-Constant C (2009) beta1 integrin maintains integrity of the embryonic neocortical stem cell niche. PLoS biol 7(8):e1000176. doi: 10.1371/journal.pbio.1000176 PubMedGoogle Scholar
  60. Lu Q, Paredes M, Medina M, Zhou J, Cavallo R, Peifer M, Orecchio L, Kosik KS (1999) Delta-catenin, an adhesive junction-associated protein which promotes cell scattering. J Cell Biol 144(3):519–532PubMedGoogle Scholar
  61. Lui JH, Hansen DV, Kriegstein AR (2011) Development and evolution of the human neocortex. Cell 146(1):18–36. doi: 10.1016/j.cell.2011.06.030 PubMedGoogle Scholar
  62. Macdonald R, Xu Q, Barth KA, Mikkola I, Holder N, Fjose A, Krauss S, Wilson SW (1994) Regulatory gene expression boundaries demarcate sites of neuronal differentiation in the embryonic zebra fish forebrain. Neuron 13(5):1039–1053PubMedGoogle Scholar
  63. Maekawa M, Takashima N, Arai Y, Nomura T, Inokuchi K, Yuasa S, Osumi N (2005) Pax6 is required for production and maintenance of progenitor cells in postnatal hippocampal neurogenesis. Genes cells 10(10):1001–1014. doi: 10.1111/j.1365-2443.2005.00893.x PubMedGoogle Scholar
  64. Maekawa M, Iwayama Y, Nakamura K, Sato M, Toyota T, Ohnishi T, Yamada K, Miyachi T, Tsujii M, Hattori E, Maekawa N, Osumi N, Mori N, Yoshikawa T (2009) A novel missense mutation (Leu46Val) of PAX6 found in an autistic patient. Neurosci Lett 462(3):267–271. doi: 10.1016/j.neulet.2009.07.021 PubMedGoogle Scholar
  65. Maekawa M, Fujisawa H, Iwayama Y, Tamase A, Toyota T, Osumi N, Yoshikawa T (2010) Giant subependymoma developed in a patient with aniridia: analyses of PAX6 and tumor-relevant genes. Brain Pathol 20(6):1033–1041. doi: 10.1111/j.1750-3639.2010.00406.x PubMedGoogle Scholar
  66. Manuel M, Price DJ (2005) Role of Pax6 in forebrain regionalization. Brain Res Bull 66(4–6):387–393. doi: 10.1016/j.brainresbull.2005.02.006 PubMedGoogle Scholar
  67. Markl ID, Cheng J, Liang G, Shibata D, Laird PW, Jones PA (2001) Global and gene-specific epigenetic patterns in human bladder cancer genomes are relatively stable in vivo and in vitro over time. Cancer Res 61(15):5875–5884PubMedGoogle Scholar
  68. Marthiens V, Kazanis I, Moss L, Long K, Ffrench-Constant C (2010) Adhesion molecules in the stem cell niche–more than just staying in shape? J Cell Sci 123(Pt 10):1613–1622. doi: 10.1242/jcs.054312 PubMedGoogle Scholar
  69. Mastick GS, Andrews GL (2001) Pax6 regulates the identity of embryonic diencephalic neurons. Mol Cell Neurosci 17(1):190–207. doi: 10.1006/mcne.2000.0924 PubMedGoogle Scholar
  70. Mastick GS, Davis NM, Andrew GL, Easter SS Jr (1997) Pax-6 functions in boundary formation and axon guidance in the embryonic mouse forebrain. Development 124(10):1985–1997PubMedGoogle Scholar
  71. McBride DJ, Buckle A, van Heyningen V, Kleinjan DA (2011) DNaseI hypersensitivity and ultraconservation reveal novel, interdependent long-range enhancers at the complex Pax6 cis-regulatory region. PLoS One 6(12):e28616. doi: 10.1371/journal.pone.0028616 PubMedGoogle Scholar
  72. Meyer G, Goffinet AM (1998) Prenatal development of reelin-immunoreactive neurons in the human neocortex. J Comp Neurol 397(1):29–40PubMedGoogle Scholar
  73. Murakami Y, Ogasawara M, Sugahara F, Hirano S, Satoh N, Kuratani S (2001) Identification and expression of the lamprey Pax6 gene: evolutionary origin of the segmented brain of vertebrates. Development 128(18):3521–3531PubMedGoogle Scholar
  74. Nacher J, Varea E, Blasco-Ibanez JM, Castillo-Gomez E, Crespo C, Martinez-Guijarro FJ, McEwen BS (2005) Expression of the transcription factor Pax 6 in the adult rat dentate gyrus. J Neurosci Res 81(6):753–761. doi: 10.1002/jnr.20596 PubMedGoogle Scholar
  75. Nakatomi H, Kuriu T, Okabe S, Yamamoto S, Hatano O, Kawahara N, Tamura A, Kirino T, Nakafuku M (2002) Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell 110(4):429–441PubMedGoogle Scholar
  76. Nangaku M, Sato-Yoshitake R, Okada Y, Noda Y, Takemura R, Yamazaki H, Hirokawa N (1994) KIF1B, a novel microtubule plus end-directed monomeric motor protein for transport of mitochondria. Cell 79(7):1209–1220PubMedGoogle Scholar
  77. Noctor SC, Martinez-Cerdeno V, Kriegstein AR (2007) Contribution of intermediate progenitor cells to cortical histogenesis. Arch Neurol 64(5):639–642. doi: 10.1001/archneur.64.5.639 PubMedGoogle Scholar
  78. Nomura T, Osumi N (2004) Misrouting of mitral cell progenitors in the Pax6/small eye rat telencephalon. Development 131(4):787–796. doi: 10.1242/dev.00984 PubMedGoogle Scholar
  79. Nomura T, Holmberg J, Frisen J, Osumi N (2006) Pax6-dependent boundary defines alignment of migrating olfactory cortex neurons via the repulsive activity of ephrin A5. Development 133(7):1335–1345. doi: 10.1242/dev.02290 PubMedGoogle Scholar
  80. Nural HF, Mastick GS (2004) Pax6 guides a relay of pioneer longitudinal axons in the embryonic mouse forebrain. J Comp Neurol 479(4):399–409. doi: 10.1002/cne.20317 PubMedGoogle Scholar
  81. Ogawa M, Miyata T, Nakajima K, Yagyu K, Seike M, Ikenaka K, Yamamoto H, Mikoshiba K (1995) The reeler gene-associated antigen on Cajal-Retzius neurons is a crucial molecule for laminar organization of cortical neurons. Neuron 14(5):899–912PubMedGoogle Scholar
  82. O'Leary DD, Sahara S (2008) Genetic regulation of arealization of the neocortex. Curr Opin Neurobiol 18(1):90–100. doi: 10.1016/j.conb.2008.05.011 PubMedGoogle Scholar
  83. Osumi N (2001) The role of Pax6 in brain patterning. Tohoku J Exp Med 193(3):163–174PubMedGoogle Scholar
  84. Osumi N, Hirota A, Ohuchi H, Nakafuku M, Iimura T, Kuratani S, Fujiwara M, Noji S, Eto K (1997) Pax-6 is involved in the specification of hindbrain motor neuron subtype. Development 124(15):2961–2972PubMedGoogle Scholar
  85. 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 PubMedGoogle Scholar
  86. Pera EM, Kessel M (1997) Patterning of the chick forebrain anlage by the prechordal plate. Development 124(20):4153–4162PubMedGoogle Scholar
  87. Pichaud F, Desplan C (2002) Pax genes and eye organogenesis. Curr Opin Genet Dev 12(4):430–434PubMedGoogle Scholar
  88. Pinto GR, Clara CA, Santos MJ, Almeida JR, Burbano RR, Rey JA, Casartelli C (2007) Mutation analysis of gene PAX6 in human gliomas. Genet mol res 6(4):1019–1025PubMedGoogle Scholar
  89. Pontious A, Kowalczyk T, Englund C, Hevner RF (2008) Role of intermediate progenitor cells in cerebral cortex development. Dev Neurosci 30(1–3):24–32. doi: 10.1159/000109848 PubMedGoogle Scholar
  90. 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 PubMedGoogle Scholar
  91. Quinn JC, Molinek M, Nowakowski TJ, Mason JO, Price DJ (2010) Novel lines of Pax6−/− embryonic stem cells exhibit reduced neurogenic capacity without loss of viability. BMC neurosci 11:26. doi: 10.1186/1471-2202-11-26 PubMedGoogle Scholar
  92. Radakovits R, Barros CS, Belvindrah R, Patton B, Muller U (2009) Regulation of radial glial survival by signals from the meninges. J Neurosci 29(24):7694–7705. doi: 10.1523/JNEUROSCI.5537-08.2009 PubMedGoogle Scholar
  93. Radner S, Banos C, Bachay G, Li YN, Hunter DD, Brunken WJ, Yee KT (2013) Beta2 and gamma3 laminins are critical cortical basement membrane components: ablation of Lamb2 and Lamc3 genes disrupts cortical lamination and produces dysplasia. Dev Neurobiol 73(3):209–229. doi: 10.1002/dneu.22057 PubMedGoogle Scholar
  94. Reillo I, de Juan RC, Garcia-Cabezas MA, Borrell V (2011) A role for intermediate radial glia in the tangential expansion of the mammalian cerebral cortex. Cereb Cortex 21(7):1674–1694. doi: 10.1093/cercor/bhq238 PubMedGoogle Scholar
  95. Rubenstein JL (2010) Three hypotheses for developmental defects that may underlie some forms of autism spectrum disorder. Curr Opin Neurol 23(2):118–123. doi: 10.1097/WCO.0b013e328336eb13 PubMedGoogle Scholar
  96. Saffary R, Xie Z (2011) FMRP regulates the transition from radial glial cells to intermediate progenitor cells during neocortical development. J Neurosci 31(4):1427–1439. doi: 10.1523/JNEUROSCI.4854-10.2011 PubMedGoogle Scholar
  97. Sakayori N, Kikkawa T, Osumi N (2012) Reduced proliferation and excess astrogenesis of Pax6 heterozygous neural stem/progenitor cells. Neurosci Res 74(2):116–121. doi: 10.1016/j.neures.2012.08.004 PubMedGoogle Scholar
  98. Sakurai K, Osumi N (2008) The neurogenesis-controlling factor, Pax6, inhibits proliferation and promotes maturation in murine astrocytes. J Neurosci 28(18):4604–4612. doi: 10.1523/JNEUROSCI.5074-07.2008 PubMedGoogle Scholar
  99. Sansom SN, Griffiths DS, Faedo A, Kleinjan DJ, Ruan Y, Smith J, van Heyningen V, Rubenstein JL, Livesey FJ (2009) The level of the transcription factor Pax6 is essential for controlling the balance between neural stem cell self-renewal and neurogenesis. PLoS Genet 5(6):e1000511. doi: 10.1371/journal.pgen.1000511 PubMedGoogle Scholar
  100. Scardigli R, Schuurmans C, Gradwohl G, Guillemot F (2001) Crossregulation between Neurogenin2 and pathways specifying neuronal identity in the spinal cord. Neuron 31(2):203–217. doi:S0896-6273(01)00358-0 [pii]PubMedGoogle Scholar
  101. Scardigli R, Baumer N, Gruss P, Guillemot F, Le Roux I (2003) Direct and concentration-dependent regulation of the proneural gene Neurogenin2 by Pax6. Development 130(14):3269–3281PubMedGoogle Scholar
  102. Shimoda Y, Tajima Y, Osanai T, Katsume A, Kohara M, Kudo T, Narimatsu H, Takashima N, Ishii Y, Nakamura S, Osumi N, Sanai Y (2002) Pax6 controls the expression of Lewis × epitope in the embryonic forebrain by regulating alpha 1,3-fucosyltransferase IX expression. J Biol Chem 277(3):2033–2039. doi: 10.1074/jbc.M108495200 PubMedGoogle Scholar
  103. Sirko S, Neitz A, Mittmann T, Horvat-Brocker A, von Holst A, Eysel UT, Faissner A (2009) Focal laser-lesions activate an endogenous population of neural stem/progenitor cells in the adult visual cortex. Brain 132(Pt 8):2252–2264. doi: 10.1093/brain/awp043 PubMedGoogle Scholar
  104. Stoykova A, Gruss P (1994) Roles of Pax-genes in developing and adult brain as suggested by expression patterns. J Neurosci 14(3 Pt 2):1395–1412PubMedGoogle Scholar
  105. Stoykova A, Gotz M, Gruss P, Price J (1997) Pax6-dependent regulation of adhesive patterning, R-cadherin expression and boundary formation in developing forebrain. Development 124(19):3765–3777PubMedGoogle Scholar
  106. Talamillo A, Quinn JC, Collinson JM, Caric D, Price DJ, West JD, Hill RE (2003) Pax6 regulates regional development and neuronal migration in the cerebral cortex. Dev Biol 255(1):151–163PubMedGoogle Scholar
  107. 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 PubMedGoogle Scholar
  108. Tamamaki N (2002) Radial glias and radial fibers: what is the function of radial fibers? Anat Sci Int 77(1):2–11. doi: 10.1046/j.0022-7722.2002.00013.x PubMedGoogle Scholar
  109. Tang K, Rubenstein JL, Tsai SY, Tsai MJ (2012) COUP-TFII controls amygdala patterning by regulating neuropilin expression. Development 139(9):1630–1639. doi: 10.1242/dev.075564 PubMedGoogle Scholar
  110. Ton CC, Hirvonen H, Miwa H, Weil MM, Monaghan P, Jordan T, van Heyningen V, Hastie ND, Meijers-Heijboer H, Drechsler M et al (1991) Positional cloning and characterization of a paired box- and homeobox-containing gene from the aniridia region. Cell 67(6):1059–1074PubMedGoogle Scholar
  111. Tong Y, Shen J (2009) alpha-synuclein and LRRK2: partners in crime. Neuron 64(6):771–773. doi: 10.1016/j.neuron.2009.12.017 PubMedGoogle Scholar
  112. Tsui D, Vessey JP, Tomita H, Kaplan DR, Miller FD (2013) FoxP2 regulates neurogenesis during embryonic cortical development. J Neurosci 33(1):244–258. doi: 10.1523/JNEUROSCI.1665-12.2013 PubMedGoogle Scholar
  113. Tsunekawa Y, Osumi N (2012) How to keep proliferative neural stem/progenitor cells: a critical role of asymmetric inheritance of cyclin D2. Cell Cycle 11(19):3550–3554. doi: 10.4161/cc.21500 PubMedGoogle Scholar
  114. Tsunekawa Y, Britto JM, Takahashi M, Polleux F, Tan SS, Osumi N (2012) Cyclin D2 in the basal process of neural progenitors is linked to non-equivalent cell fates. EMBO J 31(8):1879–1892. doi: 10.1038/emboj.2012.43 PubMedGoogle Scholar
  115. 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 PubMedGoogle Scholar
  116. Umeda T, Takashima N, Nakagawa R, Maekawa M, Ikegami S, Yoshikawa T, Kobayashi K, Okanoya K, Inokuchi K, Osumi N (2010) Evaluation of Pax6 mutant rat as a model for autism. PLoS One 5(12):e15500. doi: 10.1371/journal.pone.0015500 PubMedGoogle Scholar
  117. Vergano-Vera E, Yusta-Boyo MJ, de Castro F, Bernad A, de Pablo F, Vicario-Abejon C (2006) Generation of GABAergic and dopaminergic interneurons from endogenous embryonic olfactory bulb precursor cells. Development 133(21):4367–4379. doi: 10.1242/dev.02601 PubMedGoogle Scholar
  118. von Holst A, Egbers U, Prochiantz A, Faissner A (2007) Neural stem/progenitor cells express 20 tenascin C isoforms that are differentially regulated by Pax6. J Biol Chem 282(12):9172–9181. doi: 10.1074/jbc.M608067200 Google Scholar
  119. Walther C, Gruss P (1991) Pax-6, a murine paired box gene, is expressed in the developing CNS. Development 113(4):1435–1449PubMedGoogle Scholar
  120. 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):627–635PubMedGoogle Scholar
  121. Wei B, Nie Y, Li X, Wang C, Ma T, Huang Z, Tian M, Sun C, Cai Y, You Y, Liu F, Yang Z (2011) Emx1-expressing neural stem cells in the subventricular zone give rise to new interneurons in the ischemic injured striatum. Eur J Neurosci 33(5):819–830. doi: 10.1111/j.1460-9568.2010.07570.x PubMedGoogle Scholar
  122. Weimann JM, Zhang YA, Levin ME, Devine WP, Brulet P, McConnell SK (1999) Cortical neurons require Otx1 for the refinement of exuberant axonal projections to subcortical targets. Neuron 24(4):819–831PubMedGoogle Scholar
  123. Wen J, Hu Q, Li M, Wang S, Zhang L, Chen Y, Li L (2008) Pax6 directly modulate Sox2 expression in the neural progenitor cells. Neuroreport 19(4):413–417. doi: 10.1097/WNR.0b013e3282f64377 PubMedGoogle Scholar
  124. Winslow AR, Chen CW, Corrochano S, Acevedo-Arozena A, Gordon DE, Peden AA, Lichtenberg M, Menzies FM, Ravikumar B, Imarisio S, Brown S, O'Kane CJ, Rubinsztein DC (2010) alpha-Synuclein impairs macroautophagy: implications for Parkinson's disease. J Cell Biol 190(6):1023–1037. doi: 10.1083/jcb.201003122 PubMedGoogle Scholar
  125. Wu X, Rauch TA, Zhong X, Bennett WP, Latif F, Krex D, Pfeifer GP (2010) CpG island hypermethylation in human astrocytomas. Cancer Res 70(7):2718–2727. doi: 10.1158/0008-5472.CAN-09-3631 PubMedGoogle Scholar
  126. Xie Q, Yang Y, Huang J, Ninkovic J, Walcher T, Wolf L, Vitenzon A, Zheng D, Gotz M, Beebe DC, Zavadil J, Cvekl A (2013) Pax6 interactions with chromatin and identification of its novel direct target genes in lens and forebrain. PLoS One 8(1):e54507. doi: 10.1371/journal.pone.0054507 PubMedGoogle Scholar
  127. Xu S, Han JC, Morales A, Menzie CM, Williams K, Fan YS (2008) Characterization of 11p14-p12 deletion in WAGR syndrome by array CGH for identifying genes contributing to mental retardation and autism. Cytogenet Genome Res 122(2):181–187. doi: 10.1159/000172086 PubMedGoogle Scholar
  128. Zhang X, Heaney S, Maas RL (2003) Cre-loxp fate-mapping of Pax6 enhancer active retinal and pancreatic progenitors. Genesis 35(1):22–30. doi: 10.1002/gene.10160 PubMedGoogle Scholar
  129. Zhang C, Wu H, Zhu X, Wang Y, Guo J (2011) Role of transcription factors in neurogenesis after cerebral ischemia. Rev Neurosci 22(4):457–465. doi: 10.1515/RNS.2011.034 PubMedGoogle Scholar
  130. Zhou YH, Tan F, Hess KR, Yung WK (2003) The expression of PAX6, PTEN, vascular endothelial growth factor, and epidermal growth factor receptor in gliomas: relationship to tumor grade and survival. Clin cancer res 9(9):3369–3375PubMedGoogle Scholar
  131. Zhou YH, Wu X, Tan F, Shi YX, Glass T, Liu TJ, Wathen K, Hess KR, Gumin J, Lang F, Yung WK (2005) PAX6 suppresses growth of human glioblastoma cells. J Neurooncol 71(3):223–229. doi: 10.1007/s11060-004-1720-4 PubMedGoogle Scholar

Copyright information

© Springer Japan 2013

Authors and Affiliations

  1. 1.Division of Developmental Neuroscience, United Centers for Advanced Research and Translational Medicine (ART), Graduate School of MedicineTohoku UniversitySendaiJapan

Personalised recommendations