Proneural Proteins and the Development of the Cerebral Cortex



Proneural transcription factors are key regulators of neurogenesis. This chapter focuses on the proneural proteins Ascl1, Neurog1 and Neurog2 and their multiple roles in development of the mammalian cerebral cortex. The first part of the chapter considers the different aspects of telencephalic development that are regulated by proneural proteins, including the neuronal versus glial fate decision, the specification of glutamatergic and GABAergic neuronal phenotypes, and the radial migration, dendritic morphogenesis and axonal projection patterning of cortical neurons. The second part turns to the molecular mechanisms through which proneural proteins exert their activities and discusses the regulation of their expression and activity, the identification of the many genes they regulate and finally the nature of the transcription factors and cofactors that they interact with to regulate gene expression. Together, this chapter illustrates how studies focused on the functions and modes of action of a small group of proteins have greatly improved our general understanding of cortical development.


Radial Migration Proneural Gene Medial Ganglionic Eminence Ventral Telencephalon Cortical Progenitor 
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.



We thank Wai Han Yau for the artwork. Research in the lab of JH is supported by grants from the National Health and Medical Research Council of Australia. Research in the lab of FG is supported in part by a grant in aid from the Medical Research Council, UK.


  1. Ali F, Hindley C, McDowell G, Deibler R, Jones A, Kirschner M, Guillemot F, Philpott A (2011) Cell cycle-regulated multi-site phosphorylation of Neurogenin 2 coordinates cell cycling with differentiation during neurogenesis. Development 138(19):4267–4277PubMedCrossRefGoogle Scholar
  2. Asprer JS, Lee B, Wu CS, Vadakkan T, Dickinson ME, Lu HC, Lee SK (2011) LMO4 functions as a co-activator of neurogenin 2 in the developing cortex. Development 138(13):2823–2832PubMedCrossRefGoogle Scholar
  3. Berninger B, Guillemot F, Gotz M (2007) Directing neurotransmitter identity of neurones derived from expanded adult neural stem cells. Eur J Neurosci 25(9):2581–2590PubMedCrossRefGoogle Scholar
  4. Bertrand N, Castro DS, Guillemot F (2002) Proneural genes and the specification of neural cell types. Nat Rev Neurosci 3(7):517–530PubMedCrossRefGoogle Scholar
  5. Brill MS, Ninkovic J, Winpenny E, Hodge RD, Ozen I, Yang R, Lepier A, Gascon S, Erdelyi F, Szabo G et al (2009) Adult generation of glutamatergic olfactory bulb interneurons. Nat Neurosci 12(12):1524–1533PubMedCrossRefGoogle Scholar
  6. Britz O, Mattar P, Nguyen L, Langevin LM, Zimmer C, Alam S, Guillemot F, Schuurmans C (2006) A role for proneural genes in the maturation of cortical progenitor cells. Cereb Cortex 16(Suppl 1):i138–i151PubMedCrossRefGoogle Scholar
  7. Casarosa S, Fode C, Guillemot F (1999) Mash1 regulates neurogenesis in the ventral telencephalon. Development 126(3):525–534PubMedGoogle Scholar
  8. Castro DS, Skowronska-Krawczyk D, Armant O, Donaldson IJ, Parras C, Hunt C, Critchley JA, Nguyen L, Gossler A, Gottgens B et al (2006) Proneural bHLH and Brn proteins coregulate a neurogenic program through cooperative binding to a conserved DNA motif. Dev Cell 11(6):831–844PubMedCrossRefGoogle Scholar
  9. Castro DS, Martynoga B, Parras C, Ramesh V, Pacary E, Johnston C, Drechsel D, Lebel-Potter M, Garcia LG, Hunt C et al (2011) A novel function of the proneural factor Ascl1 in progenitor proliferation identified by genome-wide characterization of its targets. Genes Dev 25(9):930–945PubMedCrossRefGoogle Scholar
  10. Farah MH, Olson JM, Sucic HB, Hume RI, Tapscott SJ, Turner DL (2000) Generation of neurons by transient expression of neural bHLH proteins in mammalian cells. Development 127(4):693–702PubMedGoogle Scholar
  11. Fode C, Ma Q, Casarosa S, Ang SL, Anderson DJ, Guillemot F (2000) A role for neural determination genes in specifying the dorsoventral identity of telencephalic neurons. Genes Dev 14(1):67–80PubMedGoogle Scholar
  12. Ge W, He F, Kim KJ, Blanchi B, Coskun V, Nguyen L, Wu X, Zhao J, Heng JI, Martinowich K et al (2006) Coupling of cell migration with neurogenesis by proneural bHLH factors. Proc Natl Acad Sci U S A 103(5):1319–1324PubMedCrossRefGoogle Scholar
  13. Gohlke JM, Armant O, Parham FM, Smith MV, Zimmer C, Castro DS, Nguyen L, Parker JS, Gradwohl G, Portier CJ et al (2008) Characterization of the proneural gene regulatory network during mouse telencephalon development. BMC Biol 6:15PubMedCrossRefGoogle Scholar
  14. Guillemot F, Joyner AL (1993) Dynamic expression of the murine Achaete-Scute homologue Mash-1 in the developing nervous system. Mech Dev 42(3):171–185PubMedCrossRefGoogle Scholar
  15. Hand R, Polleux F (2011) Neurogenin2 regulates the initial axon guidance of cortical pyramidal neurons projecting medially to the corpus callosum. Neural Dev 6:30PubMedCrossRefGoogle Scholar
  16. Hand R, Bortone D, Mattar P, Nguyen L, Heng JI, Guerrier S, Boutt E, Peters E, Barnes AP, Parras C et al (2005) Phosphorylation of Neurogenin2 specifies the migration properties and the dendritic morphology of pyramidal neurons in the neocortex. Neuron 48(1):45–62PubMedCrossRefGoogle Scholar
  17. Heinrich C, Blum R, Gascon S, Masserdotti G, Tripathi P, Sanchez R, Tiedt S, Schroeder T, Gotz M, Berninger B (2010) Directing astroglia from the cerebral cortex into subtype specific functional neurons. PLoS Biol 8(5):e1000373PubMedCrossRefGoogle Scholar
  18. Heng JI, Nguyen L, Castro DS, Zimmer C, Wildner H, Armant O, Skowronska-Krawczyk D, Bedogni F, Matter JM, Hevner R et al (2008) Neurogenin 2 controls cortical neuron migration through regulation of Rnd2. Nature 455(7209):114–118PubMedCrossRefGoogle Scholar
  19. Henke RM, Meredith DM, Borromeo MD, Savage TK, Johnson JE (2009) Ascl1 and Neurog2 form novel complexes and regulate Delta-like3 (Dll3) expression in the neural tube. Dev Biol 328(2):529–540PubMedCrossRefGoogle Scholar
  20. Hindley C, Ali F, McDowell G, Cheng K, Jones A, Guillemot F, Philpott A (2012) Post-translational modification of Ngn2 differentially affects transcription of distinct targets to regulate the balance between progenitor maintenance and differentiation. Development 139(10):1718–1723PubMedCrossRefGoogle Scholar
  21. Hirabayashi Y, Itoh Y, Tabata H, Nakajima K, Akiyama T, Masuyama N, Gotoh Y (2004) The Wnt/beta-catenin pathway directs neuronal differentiation of cortical neural precursor cells. Development 131(12):2791–2801PubMedCrossRefGoogle Scholar
  22. Hirabayashi Y, Suzki N, Tsuboi M, Endo TA, Toyoda T, Shinga J, Koseki H, Vidal M, Gotoh Y (2009) Polycomb limits the neurogenic competence of neural precursor cells to promote astrogenic fate transition. Neuron 63(5):600–613PubMedCrossRefGoogle Scholar
  23. Hu Y, Wang T, Stormo GD, Gordon JI (2004) RNA interference of achaete-scute homolog 1 in mouse prostate neuroendocrine cells reveals its gene targets and DNA binding sites. Proc Natl Acad Sci U S A 101(15):5559–5564PubMedCrossRefGoogle Scholar
  24. Kageyama R, Ohtsuka T, Shimojo H, Imayoshi I (2008) Dynamic Notch signaling in neural progenitor cells and a revised view of lateral inhibition. Nat Neurosci 11(11):1247–1251PubMedCrossRefGoogle Scholar
  25. Knuckles P, Vogt MA, Lugert S, Milo M, Chong MM, Hautbergue GM, Wilson SA, Littman DR, Taylor V (2012) Drosha regulates neurogenesis by controlling neurogenin 2 expression independent of microRNAs. Nat Neurosci 15(7):962–969PubMedCrossRefGoogle Scholar
  26. Kovach C, Dixit R, Li S, Mattar P, Wilkinson G, Elsen GE, Kurrasch DM, Hevner RF, Schuurmans C (2012) Neurog2 simultaneously activates and represses alternative gene expression programs in the developing neocortex. Cereb cortex 23(8):1884–1900Google Scholar
  27. Koyano-Nakagawa N, Wettstein D, Kintner C (1999) Activation of Xenopus genes required for lateral inhibition and neuronal differentiation during primary neurogenesis. Mol Cell Neurosci 14(4–5):327–339PubMedCrossRefGoogle Scholar
  28. Lee SK, Pfaff SL (2003) Synchronization of neurogenesis and motor neuron specification by direct coupling of bHLH and homeodomain transcription factors. Neuron 38(5):731–745PubMedCrossRefGoogle Scholar
  29. Lee JE, Hollenberg SM, Snider L, Turner DL, Lipnick N, Weintraub H (1995) Conversion of Xenopus ectoderm into neurons by NeuroD, a basic helix-loop-helix protein. Science 268(5212):836–844PubMedCrossRefGoogle Scholar
  30. Lee S, Lee B, Lee JW, Lee SK (2009) Retinoid signaling and neurogenin2 function are coupled for the specification of spinal motor neurons through a chromatin modifier CBP. Neuron 62(5):641–654PubMedCrossRefGoogle Scholar
  31. Li S, Mattar P, Zinyk D, Singh K, Chaturvedi CP, Kovach C, Dixit R, Kurrasch DM, Ma YC, Chan JA et al (2012) GSK3 temporally regulates neurogenin 2 proneural activity in the neocortex. J neurosci 32(23):7791–7805PubMedCrossRefGoogle Scholar
  32. Louvi A, Artavanis-Tsakonas S (2006) Notch signalling in vertebrate neural development. Nat Rev Neurosci 7(2):93–102PubMedCrossRefGoogle Scholar
  33. Ma YC, Song MR, Park JP, Henry Ho HY, Hu L, Kurtev MV, Zieg J, Ma Q, Pfaff SL, Greenberg ME (2008) Regulation of motor neuron specification by phosphorylation of neurogenin 2. Neuron 58(1):65–77PubMedCrossRefGoogle Scholar
  34. Marin O, Anderson SA, Rubenstein JL (2000) Origin and molecular specification of striatal interneurons. J neurosci 20(16):6063–6076PubMedGoogle Scholar
  35. Marro S, Pang ZP, Yang N, Tsai MC, Qu K, Chang HY, Sudhof TC, Wernig M (2011) Direct lineage conversion of terminally differentiated hepatocytes to functional neurons. Cell Stem Cell 9(4):374–382PubMedCrossRefGoogle Scholar
  36. Martynoga B, Drechsel D, Guillemot F (2012) Molecular control of neurogenesis: a view from the mammalian cerebral cortex. Cold Spring Harb Perspect Biol 4(10). doi: 10.1011/cshperspect.a008359
  37. Massari ME, Murre C (2000) Helix-Loop-Helix proteins: regulators of transcription in eucaryotic organisms. Mol Cell Biol 20(3):429–440PubMedCrossRefGoogle Scholar
  38. Mattar P, Britz O, Johannes C, Nieto M, Ma L, Rebeyka A, Klenin N, Polleux F, Guillemot F, Schuurmans C (2004) A screen for downstream effectors of Neurogenin2 in the embryonic neocortex. Dev Biol 273(2):373–389PubMedCrossRefGoogle Scholar
  39. Mattar P, Langevin LM, Markham K, Klenin N, Shivji S, Zinyk D, Schuurmans C (2008) Basic helix-loop-helix transcription factors cooperate to specify a cortical projection neuron identity. Mol Cell Biol 28(5):1456–1469PubMedCrossRefGoogle Scholar
  40. Nakashima K, Takizawa T, Ochiai W, Yanagisawa M, Hisatsune T, Nakafuku M, Miyazono K, Kishimoto T, Kageyama R, Taga T (2001) BMP2-mediated alteration in the developmental pathway of fetal mouse brain cells from neurogenesis to astrocytogenesis. Proc Natl Acad Sci U S A 98(10):5868–5873PubMedCrossRefGoogle Scholar
  41. Nguyen L, Besson A, Heng JI, Schuurmans C, Teboul L, Parras C, Philpott A, Roberts JM, Guillemot F (2006) p27kip1 independently promotes neuronal differentiation and migration in the cerebral cortex. Genes Dev 20(11):1511–1524PubMedCrossRefGoogle Scholar
  42. Nieto M, Schuurmans C, Britz O, Guillemot F (2001) Neural bHLH genes control the neuronal versus glial fate decision in cortical progenitors. Neuron 29(2):401–413PubMedCrossRefGoogle Scholar
  43. Ochiai W, Nakatani S, Takahara T, Kainuma M, Masaoka M, Minobe S, Namihira M, Nakashima K, Sakakibara A, Ogawa M et al (2009) Periventricular notch activation and asymmetric Ngn2 and Tbr2 expression in pair-generated neocortical daughter cells. Mol Cell Neurosci 40(2):225–233PubMedCrossRefGoogle Scholar
  44. Pacary E, Heng J, Azzarelli R, Riou P, Castro D, Lebel-Potter M, Parras C, Bell DM, Ridley AJ, Parsons M et al (2011) Proneural transcription factors regulate different steps of cortical neuron migration through Rnd-mediated inhibition of RhoA signaling. Neuron 69(6):1069–1084PubMedCrossRefGoogle Scholar
  45. Pang ZP, Yang N, Vierbuchen T, Ostermeier A, Fuentes DR, Yang TQ, Citri A, Sebastiano V, Marro S, Sudhof TC et al (2011) Induction of human neuronal cells by defined transcription factors. Nature 476(7359):220–223PubMedGoogle Scholar
  46. Parras CM, Schuurmans C, Scardigli R, Kim J, Anderson DJ, Guillemot F (2002) Divergent functions of the proneural genes Mash1 and Ngn2 in the specification of neuronal subtype identity. Genes Dev 16(3):324–338PubMedCrossRefGoogle Scholar
  47. Parras CM, Galli R, Britz O, Soares S, Galichet C, Battiste J, Johnson JE, Nakafuku M, Vescovi A, Guillemot F (2004) Mash1 specifies neurons and oligodendrocytes in the postnatal brain. EMBO J 23(22):4495–4505PubMedCrossRefGoogle Scholar
  48. Parras CM, Hunt C, Sugimori M, Nakafuku M, Rowitch D, Guillemot F (2007) The proneural gene Mash1 specifies an early population of telencephalic oligodendrocytes. J neurosci 27(16):4233–4242PubMedCrossRefGoogle Scholar
  49. Petryniak MA, Potter GB, Rowitch DH, Rubenstein JL (2007) Dlx1 and Dlx2 control neuronal versus oligodendroglial cell fate acquisition in the developing forebrain. Neuron 55(3):417–433PubMedCrossRefGoogle Scholar
  50. Poitras L, Ghanem N, Hatch G, Ekker M (2007) The proneural determinant MASH1 regulates forebrain Dlx1/2 expression through the I12b intergenic enhancer. Development 134(9):1755–1765PubMedCrossRefGoogle Scholar
  51. Riou P, Villalonga P, Ridley AJ (2010) Rnd proteins: multifunctional regulators of the cytoskeleton and cell cycle progression. BioEssays 32(11):986–992PubMedCrossRefGoogle Scholar
  52. Rouaux C, Arlotta P (2010) Fezf2 directs the differentiation of corticofugal neurons from striatal progenitors in vivo. Nat Neurosci 13(11):1345–1347PubMedCrossRefGoogle Scholar
  53. Roybon L, Deierborg T, Brundin P, Li JY (2009a) Involvement of Ngn2, Tbr and NeuroD proteins during postnatal olfactory bulb neurogenesis. Eur J Neurosci 29(2):232–243PubMedCrossRefGoogle Scholar
  54. Roybon L, Hjalt T, Stott S, Guillemot F, Li JY, Brundin P (2009b) Neurogenin2 directs granule neuroblast production and amplification while NeuroD1 specifies neuronal fate during hippocampal neurogenesis. PLoS One 4(3):e4779PubMedCrossRefGoogle Scholar
  55. Scardigli R, Schuurmans C, Gradwohl G, Guillemot F (2001) Crossregulation between Neurogenin2 and pathways specifying neuronal identity in the spinal cord. Neuron 31(2):203–217PubMedCrossRefGoogle Scholar
  56. 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):3269–3281PubMedCrossRefGoogle Scholar
  57. Schuurmans C, Armant O, Nieto M, Stenman JM, Britz O, Klenin N, Brown C, Langevin LM, Seibt J, Tang H et al (2004) Sequential phases of cortical specification involve Neurogenin-dependent and -independent pathways. EMBO J 23(14):2892–2902PubMedCrossRefGoogle Scholar
  58. Seibt J, Schuurmans C, Gradwhol G, Dehay C, Vanderhaeghen P, Guillemot F, Polleux F (2003) Neurogenin2 specifies the connectivity of thalamic neurons by controlling axon responsiveness to intermediate target cues. Neuron 39(3):439–452PubMedCrossRefGoogle Scholar
  59. Seo S, Richardson GA, Kroll KL (2005) The SWI/SNF chromatin remodeling protein Brg1 is required for vertebrate neurogenesis and mediates transactivation of Ngn and NeuroD. Development 132(1):105–115PubMedCrossRefGoogle Scholar
  60. Seo S, Lim JW, Yellajoshyula D, Chang LW, Kroll KL (2007) Neurogenin and NeuroD direct transcriptional targets and their regulatory enhancers. EMBO J 26(24):5093–5108PubMedCrossRefGoogle Scholar
  61. Shimojo H, Ohtsuka T, Kageyama R (2008) Oscillations in notch signaling regulate maintenance of neural progenitors. Neuron 58(1):52–64PubMedCrossRefGoogle Scholar
  62. Sugimori M, Nagao M, Parras CM, Nakatani H, Lebel M, Guillemot F, Nakafuku M (2008) Ascl1 is required for oligodendrocyte development in the spinal cord. Development 135(7):1271–1281PubMedCrossRefGoogle Scholar
  63. Sun Y, Nadal-Vicens M, Misono S, Lin MZ, Zubiaga A, Hua X, Fan G, Greenberg ME (2001) Neurogenin promotes neurogenesis and inhibits glial differentiation by independent mechanisms. Cell 104(3):365–376PubMedCrossRefGoogle Scholar
  64. Thaler JP, Lee SK, Jurata LW, Gill GN, Pfaff SL (2002) LIM factor Lhx3 contributes to the specification of motor neuron and interneuron identity through cell-type-specific protein-protein interactions. Cell 110(2):237–249PubMedCrossRefGoogle Scholar
  65. Tomita K, Moriyoshi K, Nakanishi S, Guillemot F, Kageyama R (2000) Mammalian achaete-scute and atonal homologs regulate neuronal versus glial fate determination in the central nervous system. EMBO J 19(20):5460–5472PubMedCrossRefGoogle Scholar
  66. Vierbuchen T, Ostermeier A, Pang ZP, Kokubu Y, Sudhof TC, Wernig M (2010) Direct conversion of fibroblasts to functional neurons by defined factors. Nature 463(7284):1035–1041PubMedCrossRefGoogle Scholar
  67. Vosper JM, McDowell GS, Hindley CJ, Fiore-Heriche CS, Kucerova R, Horan I, Philpott A (2009) Ubiquitylation on canonical and non-canonical sites targets the transcription factor neurogenin for ubiquitin-mediated proteolysis. J Biol Chem 284(23):15458–15468PubMedCrossRefGoogle Scholar
  68. Wang B, Waclaw RR, Allen ZJ 2nd, Guillemot F, Campbell K (2009) Ascl1 is a required downstream effector of Gsx gene function in the embryonic mouse telencephalon. Neural Dev 4:5PubMedCrossRefGoogle Scholar
  69. Winpenny E, Lebel-Potter M, Fernandez ME, Brill MS, Gotz M, Guillemot F, Raineteau O (2011) Sequential generation of olfactory bulb glutamatergic neurons by Neurog2-expressing precursor cells. Neural Dev 6:12PubMedCrossRefGoogle Scholar

Copyright information

© Springer Japan 2013

Authors and Affiliations

  1. 1.Australian Regenerative Medicine InstituteMonash UniversityClaytonAustralia
  2. 2.Division of Molecular NeurobiologyMRC-National Institute for Medical ResearchLondonUK

Personalised recommendations