Skip to main content

Advertisement

Log in

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

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  1. Miller FD, Gauthier AS (2007) Timing is everything: making neurons versus glia in the developing cortex. Neuron 54(3):357–369. https://doi.org/10.1016/j.neuron.2007.04.019

    Article  CAS  PubMed  Google Scholar 

  2. 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 

  3. Rakic P (1988) Specification of cerebral cortical areas. Science 241(4862):170–176

    Article  CAS  PubMed  Google Scholar 

  4. Takahashi T, Nowakowski RS, Caviness VS Jr (1997) The mathematics of neocortical neuronogenesis. Dev Neurosci 19(1):17–22

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1093/cercor/bhm238

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1038/nn.2168

    Article  CAS  PubMed  Google Scholar 

  7. Hanashima C, Li SC, Shen L, Lai E, Fishell G (2004) Foxg1 suppresses early cortical cell fate. Science 303(5654):56–59. https://doi.org/10.1126/science.1090674

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1523/JNEUROSCI.4892-10.2011

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1093/cercor/bhs252

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1186/s13041-016-0242-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Rowitch DH, Kriegstein AR (2010) Developmental genetics of vertebrate glial-cell specification. Nature 468(7321):214–222. https://doi.org/10.1038/nature09611

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.neuron.2006.11.019

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.neuron.2012.01.024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Nagao M, Ogata T, Sawada Y, Gotoh Y (2016) Zbtb20 promotes astrocytogenesis during neocortical development. Nat Commun 7:11102. https://doi.org/10.1038/ncomms11102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/j.devcel.2008.12.014

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.stemcr.2015.06.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1073/pnas.1315567111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1002/cne.21205

    Article  CAS  PubMed  Google Scholar 

  19. Bayer SA (1983) 3H-Thymidine-radiographic studies of neurogenesis in the rat olfactory bulb. Exp Brain Res 50(2–3):329–340

    CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1002/cne.901340304

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1038/nn.2416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):3759–3771

    CAS  PubMed  Google Scholar 

  23. Altman J, Das GD (1965) Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol 124(3):319–335

    Article  CAS  PubMed  Google Scholar 

  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):14895–14900

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1242/dev.000265

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1093/cercor/bhp261

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1093/cercor/bhs400

    Article  PubMed  Google Scholar 

  28. Rosenthal EH, Tonchev AB, Stoykova A, Chowdhury K (2012) Regulation of archicortical arealization by the transcription factor Zbtb20. Hippocampus 22(11):2144–2156. https://doi.org/10.1002/hipo.22035

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1073/pnas.0912315107

    Article  PubMed  PubMed Central  Google Scholar 

  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):85–94

    Article  CAS  PubMed  Google Scholar 

  31. Soriano P (1999) Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat Genet 21(1):70–71. https://doi.org/10.1038/5007

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.expneurol.2015.07.023

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1006/dbio.1993.1297

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1186/1749-8104-6-12

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/j.neuron.2009.07.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/j.neuron.2006.01.018

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1007/s10735-007-9115-4

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1074/jbc.M110023200

    Article  CAS  PubMed  Google Scholar 

  39. Lim DA, Alvarez-Buylla A (2014) Adult neural stem cells stake their ground. Trends Neurosci 37(10):563–571. https://doi.org/10.1016/j.tins.2014.08.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):703–716

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1002/cne.20322

    Article  CAS  PubMed  Google Scholar 

  42. Dellovade TL, Pfaff DW, Schwanzel-Fukuda M (1998) Olfactory bulb development is altered in small-eye (Sey) mice. J Comp Neurol 402(3):402–418

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.cell.2015.05.041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1038/nn.3989

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1038/nn1340

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1523/JNEUROSCI.1299-06.2006

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1523/JNEUROSCI.3454-14.2015

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1097/00004647-200404000-00009

    Article  Google Scholar 

  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):963–970

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1038/jcbfm.2010.134

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1038/nature12069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/j.stem.2015.08.002

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.stem.2008.07.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):6627–6636

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1002/glia.21033

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1523/JNEUROSCI.1360-10.2010

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1038/nn.2220

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1523/JNEUROSCI.1398-12.2012

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1371/journal.pone.0036816

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1111/ene.13086

    Article  CAS  Google Scholar 

Download references

Funding

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).

Author information

Authors and Affiliations

Authors

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.

Corresponding authors

Correspondence to Anton B. Tonchev or Anastassia Stoykova.

Ethics declarations

Competing Interests

The authors declare that they have no competing interests.

Electronic Supplementary Material

ESM 1

(PDF 6456 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Doeppner, T.R., Herz, J., Bähr, M. et al. Zbtb20 Regulates Developmental Neurogenesis in the Olfactory Bulb and Gliogenesis After Adult Brain Injury. Mol Neurobiol 56, 567–582 (2019). https://doi.org/10.1007/s12035-018-1104-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-018-1104-y

Keywords

Navigation