Molecular Neurobiology

, Volume 56, Issue 1, pp 567–582 | Cite as

Zbtb20 Regulates Developmental Neurogenesis in the Olfactory Bulb and Gliogenesis After Adult Brain Injury

  • Thorsten R. Doeppner
  • Josephine Herz
  • Mathias Bähr
  • Anton B. TonchevEmail author
  • Anastassia StoykovaEmail author


The transcription factor (TF) Zbtb20 is important for the hippocampal specification and the regulation of neurogenesis of neocortical projection neurons. Herein, we show a critical involvement of the TF Zbtb20 in the neurogenesis of both projection neurons and interneurons of the olfactory bulb during embryonic stages. Our data indicate that the lack of Zbtb20 significantly diminishes the generation of a set of early-born Tbr2+ neurons during embryogenesis. Furthermore, we provide evidence that Zbtb20 regulates the transition between neurogenesis to gliogenesis in cortical radial glial progenitor cells at the perinatal (E18.5) stage. In the adult mammalian brain, Zbtb20 is expressed by GFAP+ neural progenitor cells (NPCs) located in the forebrain neurogenic niche, i.e., the subventricular zone (SVZ) of the lateral ventricles. Upon induction of cerebral ischemia, we found that Zbtb20 expression is upregulated in astrocytic-like cells, whereas diminishing the expression levels of Zbtb20 significantly reduces the ischemia-induced astrocytic reaction as observed in heterozygous Zbtb20 loss-of-function mice. Altogether, these results highlight the important role of the TF Zbtb20 as a temporal regulator of neurogenesis or gliogenesis, depending on the developmental context.


Zbtb20 Olfactory bulb Post-natal progenitor cell Astrocyte Stroke 


Author Contributions

A.B.T. and A.S. designed research. A.B.T., T.R.D., and J.H. performed research. T.R.D., A.S., M.B., and A.B.T. analyzed data. T.R.D., A.S., and A.B.T. wrote the manuscript.

Funding Information

This work was supported by the Max Planck Society (AS), by the DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB; AS), TÜBITAK (TRD), and the Alexander von Humboldt Foundation (ABT).

Compliance with Ethical Standards

Competing Interests

The authors declare that they have no competing interests.

Supplementary material

12035_2018_1104_MOESM1_ESM.pdf (6.3 mb)
ESM 1 (PDF 6456 kb)


  1. 1.
    Miller FD, Gauthier AS (2007) Timing is everything: making neurons versus glia in the developing cortex. Neuron 54(3):357–369. CrossRefGoogle Scholar
  2. 2.
    Angevine JB Jr, Sidman RL (1961) Autoradiographic study of cell migration during histogenesis of cerebral cortex in the mouse. Nature 192:766–768CrossRefGoogle Scholar
  3. 3.
    Rakic P (1988) Specification of cerebral cortical areas. Science 241(4862):170–176CrossRefGoogle Scholar
  4. 4.
    Takahashi T, Nowakowski RS, Caviness VS Jr (1997) The mathematics of neocortical neuronogenesis. Dev Neurosci 19(1):17–22CrossRefGoogle Scholar
  5. 5.
    Faedo A, Tomassy GS, Ruan Y, Teichmann H, Krauss S, Pleasure SJ, Tsai SY, Tsai MJ et al (2008) COUP-TFI coordinates cortical patterning, neurogenesis, and laminar fate and modulates MAPK/ERK, AKT, and beta-catenin signaling. Cereb Cortex 18(9):2117–2131. CrossRefGoogle Scholar
  6. 6.
    Naka H, Nakamura S, Shimazaki T, Okano H (2008) Requirement for COUP-TFI and II in the temporal specification of neural stem cells in CNS development. Nat Neurosci 11(9):1014–1023. CrossRefGoogle Scholar
  7. 7.
    Hanashima C, Li SC, Shen L, Lai E, Fishell G (2004) Foxg1 suppresses early cortical cell fate. Science 303(5654):56–59. CrossRefGoogle Scholar
  8. 8.
    Wang H, Ge G, Uchida Y, Luu B, Ahn S (2011) Gli3 is required for maintenance and fate specification of cortical progenitors. The Journal of neuroscience : the official journal of the Society for Neuroscience 31(17):6440–6448. CrossRefGoogle Scholar
  9. 9.
    Dominguez MH, Ayoub AE, Rakic P (2013) POU-III transcription factors (Brn1, Brn2, and Oct6) influence neurogenesis, molecular identity, and migratory destination of upper-layer cells of the cerebral cortex. Cereb Cortex 23(11):2632–2643. CrossRefGoogle Scholar
  10. 10.
    Tonchev AB, Tuoc TC, Rosenthal EH, Studer M, Stoykova A (2016) Zbtb20 modulates the sequential generation of neuronal layers in developing cortex. Mol Brain 9(1):65. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Rowitch DH, Kriegstein AR (2010) Developmental genetics of vertebrate glial-cell specification. Nature 468(7321):214–222. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Deneen B, Ho R, Lukaszewicz A, Hochstim CJ, Gronostajski RM, Anderson DJ (2006) The transcription factor NFIA controls the onset of gliogenesis in the developing spinal cord. Neuron 52(6):953–968. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Kang P, Lee HK, Glasgow SM, Finley M, Donti T, Gaber ZB, Graham BH, Foster AE et al (2012) Sox9 and NFIA coordinate a transcriptional regulatory cascade during the initiation of gliogenesis. Neuron 74(1):79–94. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Nagao M, Ogata T, Sawada Y, Gotoh Y (2016) Zbtb20 promotes astrocytogenesis during neocortical development. Nat Commun 7:11102. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Namihira M, Kohyama J, Semi K, Sanosaka T, Deneen B, Taga T, Nakashima K (2009) Committed neuronal precursors confer astrocytic potential on residual neural precursor cells. Dev Cell 16(2):245–255. CrossRefGoogle Scholar
  16. 16.
    Tsuyama J, Bunt J, Richards LJ, Iwanari H, Mochizuki Y, Hamakubo T, Shimazaki T, Okano H (2015) MicroRNA-153 regulates the acquisition of gliogenic competence by neural stem cells. Stem Cell Reports 5(3):365–377. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Naka-Kaneda H, Nakamura S, Igarashi M, Aoi H, Kanki H, Tsuyama J, Tsutsumi S, Aburatani H et al (2014) The miR-17/106-p38 axis is a key regulator of the neurogenic-to-gliogenic transition in developing neural stem/progenitor cells. Proc Natl Acad Sci U S A 111(4):1604–1609. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Parrish-Aungst S, Shipley MT, Erdelyi F, Szabo G, Puche AC (2007) Quantitative analysis of neuronal diversity in the mouse olfactory bulb. J Comp Neurol 501(6):825–836. CrossRefGoogle Scholar
  19. 19.
    Bayer SA (1983) 3H-Thymidine-radiographic studies of neurogenesis in the rat olfactory bulb. Exp Brain Res 50(2–3):329–340PubMedPubMedCentralGoogle Scholar
  20. 20.
    Hinds JW (1968) Autoradiographic study of histogenesis in the mouse olfactory bulb. I. Time of origin of neurons and neuroglia. J Comp Neurol 134(3):287–304. CrossRefGoogle Scholar
  21. 21.
    Brill MS, Ninkovic J, Winpenny E, Hodge RD, Ozen I, Yang R, Lepier A, Gascon S et al (2009) Adult generation of glutamatergic olfactory bulb interneurons. Nat Neurosci 12(12):1524–1533. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Wichterle H, Turnbull DH, Nery S, Fishell G, Alvarez-Buylla A (2001) In utero fate mapping reveals distinct migratory pathways and fates of neurons born in the mammalian basal forebrain. Development 128(19):3759–3771Google Scholar
  23. 23.
    Altman J, Das GD (1965) Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol 124(3):319–335CrossRefGoogle Scholar
  24. 24.
    Doetsch F, Alvarez-Buylla A (1996) Network of tangential pathways for neuronal migration in adult mammalian brain. Proc Natl Acad Sci U S A 93(25):14895–14900CrossRefGoogle Scholar
  25. 25.
    Nielsen JV, Nielsen FH, Ismail R, Noraberg J, Jensen NA (2007) Hippocampus-like corticoneurogenesis induced by two isoforms of the BTB-zinc finger gene Zbtb20 in mice. Development 134(6):1133–1140. CrossRefGoogle Scholar
  26. 26.
    Nielsen JV, Blom JB, Noraberg J, Jensen NA (2010) Zbtb20-induced CA1 pyramidal neuron development and area enlargement in the cerebral midline cortex of mice. Cereb Cortex 20(8):1904–1914. CrossRefGoogle Scholar
  27. 27.
    Nielsen JV, Thomassen M, Mollgard K, Noraberg J, Jensen NA (2014) Zbtb20 defines a hippocampal neuronal identity through direct repression of genes that control projection neuron development in the isocortex. Cereb Cortex 24(5):1216–1229. CrossRefGoogle Scholar
  28. 28.
    Rosenthal EH, Tonchev AB, Stoykova A, Chowdhury K (2012) Regulation of archicortical arealization by the transcription factor Zbtb20. Hippocampus 22(11):2144–2156. CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Xie Z, Ma X, Ji W, Zhou G, Lu Y, Xiang Z, Wang YX, Zhang L et al (2010) Zbtb20 is essential for the specification of CA1 field identity in the developing hippocampus. Proc Natl Acad Sci U S A 107(14):6510–6515. CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Zhuo L, Theis M, Alvarez-Maya I, Brenner M, Willecke K, Messing A (2001) hGFAP-cre transgenic mice for manipulation of glial and neuronal function in vivo. Genesis 31(2):85–94CrossRefGoogle Scholar
  31. 31.
    Soriano P (1999) Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat Genet 21(1):70–71. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Doeppner TR, Kaltwasser B, Teli MK, Sanchez-Mendoza EH, Kilic E, Bahr M, Hermann DM (2015) Post-stroke transplantation of adult subventricular zone derived neural progenitor cells—a comprehensive analysis of cell delivery routes and their underlying mechanisms. Exp Neurol 273:45–56. CrossRefGoogle Scholar
  33. 33.
    Neuman T, Keen A, Zuber MX, Kristjansson GI, Gruss P, Nornes HO (1993) Neuronal expression of regulatory helix-loop-helix factor Id2 gene in mouse. Dev Biol 160(1):186–195. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    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 6:12. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Waclaw RR, Wang B, Pei Z, Ehrman LA, Campbell K (2009) Distinct temporal requirements for the homeobox gene Gsx2 in specifying striatal and olfactory bulb neuronal fates. Neuron 63(4):451–465. CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Waclaw RR, Allen ZJ 2nd, Bell SM, Erdelyi F, Szabo G, Potter SS, Campbell K (2006) The zinc finger transcription factor Sp8 regulates the generation and diversity of olfactory bulb interneurons. Neuron 49(4):503–516. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Allen ZJ 2nd, Waclaw RR, Colbert MC, Campbell K (2007) Molecular identity of olfactory bulb interneurons: transcriptional codes of periglomerular neuron subtypes. J Mol Histol 38(6):517–525. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Mitchelmore C, Kjaerulff KM, Pedersen HC, Nielsen JV, Rasmussen TE, Fisker MF, Finsen B, Pedersen KM et al (2002) Characterization of two novel nuclear BTB/POZ domain zinc finger isoforms. Association with differentiation of hippocampal neurons, cerebellar granule cells, and macroglia. J Biol Chem 277(9):7598–7609. CrossRefGoogle Scholar
  39. 39.
    Lim DA, Alvarez-Buylla A (2014) Adult neural stem cells stake their ground. Trends Neurosci 37(10):563–571. CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Doetsch F, Caille I, Lim DA, Garcia-Verdugo JM, Alvarez-Buylla A (1999) Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97(6):703–716CrossRefGoogle Scholar
  41. 41.
    Nieto M, Monuki ES, Tang H, Imitola J, Haubst N, Khoury SJ, Cunningham J, Gotz M et al (2004) Expression of Cux-1 and Cux-2 in the subventricular zone and upper layers II–IV of the cerebral cortex. J Comp Neurol 479(2):168–180. CrossRefGoogle Scholar
  42. 42.
    Dellovade TL, Pfaff DW, Schwanzel-Fukuda M (1998) Olfactory bulb development is altered in small-eye (Sey) mice. J Comp Neurol 402(3):402–418CrossRefGoogle Scholar
  43. 43.
    Fuentealba LC, Rompani SB, Parraguez JI, Obernier K, Romero R, Cepko CL, Alvarez-Buylla A (2015) Embryonic origin of postnatal neural stem cells. Cell 161(7):1644–1655. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Furutachi S, Miya H, Watanabe T, Kawai H, Yamasaki N, Harada Y, Imayoshi I, Nelson M et al (2015) Slowly dividing neural progenitors are an embryonic origin of adult neural stem cells. Nat Neurosci 18(5):657–665. CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Garcia AD, Doan NB, Imura T, Bush TG, Sofroniew MV (2004) GFAP-expressing progenitors are the principal source of constitutive neurogenesis in adult mouse forebrain. Nat Neurosci 7(11):1233–1241. CrossRefGoogle Scholar
  46. 46.
    Menn B, Garcia-Verdugo JM, Yaschine C, Gonzalez-Perez O, Rowitch D, Alvarez-Buylla A (2006) Origin of oligodendrocytes in the subventricular zone of the adult brain. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience 26(30):7907–7918. CrossRefGoogle Scholar
  47. 47.
    Sohn J, Orosco L, Guo F, Chung SH, Bannerman P, Mills Ko E, Zarbalis K, Deng W et al (2015) The subventricular zone continues to generate corpus callosum and rostral migratory stream astroglia in normal adult mice. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience 35(9):3756–3763. CrossRefGoogle Scholar
  48. 48.
    Zhang R, Zhang Z, Wang L, Wang Y, Gousev A, Zhang L, Ho KL, Morshead C et al (2004) Activated neural stem cells contribute to stroke-induced neurogenesis and neuroblast migration toward the infarct boundary in adult rats. Journal of Cerebral Blood Flow and Metabolism: Official Journal of the International Society of Cerebral Blood Flow and Metabolism 24(4):441–448. CrossRefGoogle Scholar
  49. 49.
    Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O (2002) Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med 8(9):963–970CrossRefGoogle Scholar
  50. 50.
    Zhang RL, Chopp M, Roberts C, Jia L, Wei M, Lu M, Wang X, Pourabdollah S et al (2011) Ascl1 lineage cells contribute to ischemia-induced neurogenesis and oligodendrogenesis. Journal of Cerebral Blood Flow and Metabolism: Official Journal of the International Society of Cerebral Blood Flow and Metabolism 31(2):614–625. CrossRefGoogle Scholar
  51. 51.
    Benner EJ, Luciano D, Jo R, Abdi K, Paez-Gonzalez P, Sheng H, Warner DS, Liu C et al (2013) Protective astrogenesis from the SVZ niche after injury is controlled by Notch modulator Thbs4. Nature 497(7449):369–373. CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Faiz M, Sachewsky N, Gascon S, Bang KW, Morshead CM, Nagy A (2015) Adult neural stem cells from the subventricular zone give rise to reactive astrocytes in the cortex after stroke. Cell Stem Cell 17(5):624–634. CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Tavazoie M, Van der Veken L, Silva-Vargas V, Louissaint M, Colonna L, Zaidi B, Garcia-Verdugo JM, Doetsch F (2008) A specialized vascular niche for adult neural stem cells. Cell Stem Cell 3(3):279–288. CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Yamashita T, Ninomiya M, Hernandez Acosta P, Garcia-Verdugo JM, Sunabori T, Sakaguchi M, Adachi K, Kojima T et al (2006) Subventricular zone-derived neuroblasts migrate and differentiate into mature neurons in the post-stroke adult striatum. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience 26(24):6627–6636CrossRefGoogle Scholar
  55. 55.
    Li L, Harms KM, Ventura PB, Lagace DC, Eisch AJ, Cunningham LA (2010) Focal cerebral ischemia induces a multilineage cytogenic response from adult subventricular zone that is predominantly gliogenic. Glia 58(13):1610–1619. CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Guo F, Maeda Y, Ma J, Xu J, Horiuchi M, Miers L, Vaccarino F, Pleasure D (2010) Pyramidal neurons are generated from oligodendroglial progenitor cells in adult piriform cortex. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience 30(36):12036–12049. CrossRefGoogle Scholar
  57. 57.
    Rivers LE, Young KM, Rizzi M, Jamen F, Psachoulia K, Wade A, Kessaris N, Richardson WD (2008) PDGFRA/NG2 glia generate myelinating oligodendrocytes and piriform projection neurons in adult mice. Nat Neurosci 11(12):1392–1401. CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Salmaso N, Silbereis J, Komitova M, Mitchell P, Chapman K, Ment LR, Schwartz ML, Vaccarino FM (2012) Environmental enrichment increases the GFAP+ stem cell pool and reverses hypoxia-induced cognitive deficits in juvenile mice. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience 32(26):8930–8939. CrossRefGoogle Scholar
  59. 59.
    Honsa P, Pivonkova H, Dzamba D, Filipova M, Anderova M (2012) Polydendrocytes display large lineage plasticity following focal cerebral ischemia. PLoS One 7(5):e36816. CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Soderholm M, Almgren P, Jood K, Stanne TM, Olsson M, Ilinca A, Lorentzen E, Norrving B et al (2016) Exome array analysis of ischaemic stroke: results from a southern Swedish study. European Journal of Neurology: the Official Journal of the European Federation of Neurological Societies 23(12):1722–1728. CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Thorsten R. Doeppner
    • 1
  • Josephine Herz
    • 2
  • Mathias Bähr
    • 1
    • 3
  • Anton B. Tonchev
    • 3
    • 4
    • 5
    Email author
  • Anastassia Stoykova
    • 3
    • 4
    Email author
  1. 1.Department of NeurologyUniversity Medical Center GoettingenGoettingenGermany
  2. 2.Department of PediatricsUniversity of Duisburg-Essen Medical SchoolEssenGermany
  3. 3.Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB)GoettingenGermany
  4. 4.RG Molecular Developmental NeurobiologyMax Planck Institute of Biophysical ChemistryGoettingenGermany
  5. 5.Department of Anatomy, Histology and EmbryologyMedical University-VarnaVarnaBulgaria

Personalised recommendations