Olig2 regulates terminal differentiation and maturation of peripheral olfactory sensory neurons

Cellular and Molecular Life Sciences volume 77, pages3597–3609(2020)Cite this article

Abstract

The bHLH transcription factor Olig2 is required for sequential cell fate determination of both motor neurons and oligodendrocytes and for progenitor proliferation in the central nervous system. However, the role of Olig2 in peripheral sensory neurogenesis remains unknown. We report that Olig2 is transiently expressed in the newly differentiated olfactory sensory neurons (OSNs) and is down-regulated in the mature OSNs in mice from early gestation to adulthood. Genetic fate mapping demonstrates that Olig2-expressing cells solely give rise to OSNs in the peripheral olfactory system. Olig2 depletion does not affect the proliferation of peripheral olfactory progenitors and the fate determination of OSNs, sustentacular cells, and the olfactory ensheathing cells. However, the terminal differentiation and maturation of OSNs are compromised in either Olig2 single or Olig1/Olig2 double knockout mice, associated with significantly diminished expression of multiple OSN maturation and odorant signaling genes, including Omp, Gnal, Adcy3, and Olfr15. We further demonstrate that Olig2 binds to the E-box in the Omp promoter region to regulate its expression. Taken together, our results reveal a distinctly novel function of Olig2 in the periphery nervous system to regulate the terminal differentiation and maturation of olfactory sensory neurons.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

US$ 39.95

Tax calculation will be finalised during checkout.

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

References

  1. 1.

    Kageyama R, Ohtsuka T, Hatakeyama J, Ohsawa R (2005) Roles of bHLH genes in neural stem cell differentiation. Exp Cell Res 306(2):343–348

    PubMed  CAS  Google Scholar 

  2. 2.

    Powell LM, Jarman AP (2008) Context dependence of proneural bHLH proteins. Curr Opin Genet Dev 18(5):411–417

    PubMed  PubMed Central  CAS  Google Scholar 

  3. 3.

    Murdoch B, Roskams AJ (2007) Olfactory epithelium progenitors: insights from transgenic mice and in vitro biology. J Mol Histol 38(6):581–599

    PubMed  CAS  Google Scholar 

  4. 4.

    Sammeta N, Yu TT, Bose SC, McClintock TS (2007) Mouse olfactory sensory neurons express 10,000 genes. J Comp Neurol 502(6):1138–1156

    PubMed  CAS  Google Scholar 

  5. 5.

    Suzuki Y (2005) Expression of bHLH transcription factors and IGFs in the non-sensory patches, olfactory epithelium and vomeronasal organ. Chem Senses 30(Suppl 1):i125–i126

    PubMed  CAS  Google Scholar 

  6. 6.

    Cau E, Casarosa S, Guillemot F (2002) Mash1 and Ngn1 control distinct steps of determination and differentiation in the olfactory sensory neuron lineage. Development 129(8):1871–1880

    PubMed  CAS  Google Scholar 

  7. 7.

    Cau E, Gradwohl G, Casarosa S, Kageyama R, Guillemot F (2000) Hes genes regulate sequential stages of neurogenesis in the olfactory epithelium. Development 127(11):2323–2332

    PubMed  CAS  Google Scholar 

  8. 8.

    Rowitch DH, Lu QR, Kessaris N, Richardson WD (2002) An ‘oligarchy’ rules neural development. Trends Neurosci 25(8):417–422

    PubMed  CAS  Google Scholar 

  9. 9.

    Zhou Q, Anderson DJ (2002) The bHLH transcription factors OLIG2 and OLIG1 couple neuronal and glial subtype specification. Cell 109(1):61–73

    PubMed  CAS  Google Scholar 

  10. 10.

    Takebayashi H, Nabeshima Y, Yoshida S, Chisaka O, Ikenaka K, Nabeshima Y (2002) The basic helix–loop–helix factor olig2 is essential for the development of motoneuron and oligodendrocyte lineages. Curr Biol 12(13):1157–1163

    PubMed  CAS  Google Scholar 

  11. 11.

    Miyoshi G, Butt SJ, Takebayashi H, Fishell G (2007) Physiologically distinct temporal cohorts of cortical interneurons arise from telencephalic Olig2-expressing precursors. J Neurosci 27(29):7786–7798

    PubMed  PubMed Central  CAS  Google Scholar 

  12. 12.

    Cai J, Chen Y, Cai WH, Hurlock EC, Wu H, Kernie SG et al (2007) A crucial role for Olig2 in white matter astrocyte development. Development 134(10):1887–1899

    PubMed  CAS  Google Scholar 

  13. 13.

    Sun Y, Meijer DH, Alberta JA, Mehta S, Kane MF, Tien AC et al (2011) Phosphorylation state of Olig2 regulates proliferation of neural progenitors. Neuron 69(5):906–917

    PubMed  PubMed Central  CAS  Google Scholar 

  14. 14.

    Harrington EP, Zhao C, Fancy SP, Kaing S, Franklin RJ, Rowitch DH (2010) Oligodendrocyte PTEN is required for myelin and axonal integrity, not remyelination. Ann Neurol 68(5):703–716

    PubMed  PubMed Central  CAS  Google Scholar 

  15. 15.

    Soriano P (1999) Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat Genet 21(1):70–71

    PubMed  CAS  Google Scholar 

  16. 16.

    Wang YZ, Yamagami T, Gan Q, Wang Y, Zhao T, Hamad S et al (2011) Canonical Wnt signaling promotes the proliferation and neurogenesis of peripheral olfactory stem cells during postnatal development and adult regeneration. J Cell Sci 124(Pt 9):1553–1563

    PubMed  PubMed Central  CAS  Google Scholar 

  17. 17.

    Zhao T, Gan Q, Stokes A, Lassiter RN, Wang Y, Chan J et al (2014) beta-catenin regulates Pax3 and Cdx2 for caudal neural tube closure and elongation. Development 141(1):148–157

    PubMed  PubMed Central  CAS  Google Scholar 

  18. 18.

    Wang YP, Stokes A, Duan ZJ, Hui J, Xu Y, Chen YP et al (2016) LDL receptor-related protein 6 modulates Ret proto-oncogene signaling in renal development and cystic dysplasia. J Am Soc Nephrol 27(2):417–427

    PubMed  CAS  Google Scholar 

  19. 19.

    Song L, Li Y, Wang K, Wang YZ, Molotkov A, Gao L et al (2009) Lrp6-mediated canonical Wnt signaling is required for lip formation and fusion. Development 136(18):3161–3171

    PubMed  CAS  Google Scholar 

  20. 20.

    Gan Q, Lee A, Suzuki R, Yamagami T, Stokes A, Nguyen BC et al (2014) Pax6 mediates ss-catenin signaling for self-renewal and neurogenesis by neocortical radial glial stem cells. Stem Cells 32(1):45–58

    PubMed  PubMed Central  CAS  Google Scholar 

  21. 21.

    Ligon KL, Fancy SP, Franklin RJ, Rowitch DH (2006) Olig gene function in CNS development and disease. Glia 54(1):1–10

    PubMed  Google Scholar 

  22. 22.

    Schwob JE, Jang W, Holbrook EH, Lin B, Herrick DB, Peterson JN et al (2017) Stem and progenitor cells of the mammalian olfactory epithelium: taking poietic license. J Comp Neurol 525(4):1034–1054

    PubMed  CAS  Google Scholar 

  23. 23.

    Ellis P, Fagan BM, Magness ST, Hutton S, Taranova O, Hayashi S et al (2004) SOX2, a persistent marker for multipotential neural stem cells derived from embryonic stem cells, the embryo or the adult. Dev Neurosci 26(2–4):148–165

    PubMed  CAS  Google Scholar 

  24. 24.

    Guo Z, Packard A, Krolewski RC, Harris MT, Manglapus GL, Schwob JE (2010) Expression of pax6 and sox2 in adult olfactory epithelium. J Comp Neurol 518(21):4395–4418

    PubMed  PubMed Central  Google Scholar 

  25. 25.

    Chen Y, Miles DK, Hoang T, Shi J, Hurlock E, Kernie SG et al (2008) The basic helix–loop–helix transcription factor olig2 is critical for reactive astrocyte proliferation after cortical injury. J Neurosci 28(43):10983–10989

    PubMed  PubMed Central  CAS  Google Scholar 

  26. 26.

    Wong ST, Trinh K, Hacker B, Chan GC, Lowe G, Gaggar A et al (2000) Disruption of the type III adenylyl cyclase gene leads to peripheral and behavioral anosmia in transgenic mice. Neuron 27(3):487–497

    PubMed  CAS  Google Scholar 

  27. 27.

    Belluscio L, Gold GH, Nemes A, Axel R (1998) Mice deficient in G(olf) are anosmic. Neuron 20(1):69–81

    PubMed  CAS  Google Scholar 

  28. 28.

    Kaneko-Goto T, Yoshihara S, Miyazaki H, Yoshihara Y (2008) BIG-2 mediates olfactory axon convergence to target glomeruli. Neuron 57(6):834–846

    PubMed  CAS  Google Scholar 

  29. 29.

    Cheng LE, Reed RR (2007) Zfp423/OAZ participates in a developmental switch during olfactory neurogenesis. Neuron 54(4):547–557

    PubMed  PubMed Central  CAS  Google Scholar 

  30. 30.

    Kolterud A, Alenius M, Carlsson L, Bohm S (2004) The Lim homeobox gene Lhx2 is required for olfactory sensory neuron identity. Development 131(21):5319–5326

    PubMed  CAS  Google Scholar 

  31. 31.

    Macdonald JL, Verster A, Berndt A, Roskams AJ (2010) MBD2 and MeCP2 regulate distinct transitions in the stage-specific differentiation of olfactory receptor neurons. Mol Cell Neurosci 44(1):55–67

    PubMed  CAS  Google Scholar 

  32. 32.

    Tsai RY, Reed RR (1997) Cloning and functional characterization of Roaz, a zinc finger protein that interacts with O/E-1 to regulate gene expression: implications for olfactory neuronal development. J Neurosci 17(11):4159–4169

    PubMed  PubMed Central  CAS  Google Scholar 

  33. 33.

    Lu QR, Sun T, Zhu Z, Ma N, Garcia M, Stiles CD et al (2002) Common developmental requirement for Olig function indicates a motor neuron/oligodendrocyte connection. Cell 109(1):75–86

    PubMed  CAS  Google Scholar 

  34. 34.

    Ligon KL, Huillard E, Mehta S, Kesari S, Liu H, Alberta JA et al (2007) Olig2-regulated lineage-restricted pathway controls replication competence in neural stem cells and malignant glioma. Neuron 53(4):503–517

    PubMed  PubMed Central  CAS  Google Scholar 

  35. 35.

    Lee AC, He J, Ma M (2011) Olfactory marker protein is critical for functional maturation of olfactory sensory neurons and development of mother preference. J Neurosci 31(8):2974–2982

    PubMed  PubMed Central  CAS  Google Scholar 

  36. 36.

    Rodriguez-Gil DJ, Bartel DL, Jaspers AW, Mobley AS, Imamura F, Greer CA (2015) Odorant receptors regulate the final glomerular coalescence of olfactory sensory neuron axons. Proc Natl Acad Sci USA 112(18):5821–5826

    PubMed  CAS  Google Scholar 

  37. 37.

    Takebayashi H, Yoshida S, Sugimori M, Kosako H, Kominami R, Nakafuku M et al (2000) Dynamic expression of basic helix–loop–helix Olig family members: implication of Olig2 in neuron and oligodendrocyte differentiation and identification of a new member, Olig3. Mech Dev 99(1–2):143–148

    PubMed  CAS  Google Scholar 

  38. 38.

    Boutin C, Hardt O, de Chevigny A, Core N, Goebbels S, Seidenfaden R et al (2010) NeuroD1 induces terminal neuronal differentiation in olfactory neurogenesis. Proc Natl Acad Sci USA 107(3):1201–1206

    PubMed  CAS  Google Scholar 

  39. 39.

    Jones DT, Reed RR (1989) Golf: an olfactory neuron specific-G protein involved in odorant signal transduction. Science 244(4906):790–795

    PubMed  CAS  Google Scholar 

  40. 40.

    Qiu L, LeBel RP, Storm DR, Chen X (2016) Type 3 adenylyl cyclase: a key enzyme mediating the cAMP signaling in neuronal cilia. Int J Physiol Pathophysiol Pharmacol 8(3):95–108

    PubMed  PubMed Central  CAS  Google Scholar 

  41. 41.

    Meijer DH, Kane MF, Mehta S, Liu H, Harrington E, Taylor CM et al (2012) Separated at birth? The functional and molecular divergence of OLIG1 and OLIG2. Nat Rev Neurosci 13(12):819–831

    PubMed  PubMed Central  CAS  Google Scholar 

  42. 42.

    Zhang X, Cai J, Klueber KM, Guo Z, Lu C, Qiu M et al (2005) Induction of oligodendrocytes from adult human olfactory epithelial-derived progenitors by transcription factors. Stem Cells 23(3):442–453

    PubMed  CAS  Google Scholar 

  43. 43.

    Zhang X, Cai J, Klueber KM, Guo Z, Lu C, Winstead WI et al (2006) Role of transcription factors in motoneuron differentiation of adult human olfactory neuroepithelial-derived progenitors. Stem Cells 24(2):434–442

    PubMed  CAS  Google Scholar 

  44. 44.

    Liu Z, Hu X, Cai J, Liu B, Peng X, Wegner M et al (2007) Induction of oligodendrocyte differentiation by Olig2 and Sox10: evidence for reciprocal interactions and dosage-dependent mechanisms. Dev Biol 302(2):683–693

    PubMed  CAS  Google Scholar 

  45. 45.

    Liberia T, Martin-Lopez E, Meller SJ, Greer CA (2019) Sequential maturation of olfactory sensory neurons in the mature olfactory epithelium. eNeuro. https://doi.org/10.1523/ENEURO.0266-19.2019

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are grateful to David J. Anderson (HHMI and Caltech) for providing the Olig1/Olig2 frozen embryos, Jordan Hui, Ben Palmer, Arjun Stokes, Huan Zhao, Taylor Imai, Rebecca Duncan, Yue Liu, Santosh Kumar, Saharul Islam, Sarwat Amina and the rest of Zhou lab members for technical assistance or general support. This work was partially supported by grants from the NIH (R01DE021696, R01DE026737 and R01NS102261 to C.J.Z.), the Shriners Hospitals for Children (86600 and 85105 to C.J.Z., and postdoctoral fellowships to Y.Z.W. and R.G.), and the National Science Foundation of China (31970907 to Y.Z.W.). Q.G. and T.Y. received postdoctoral fellowships from the California Institute for Regenerative Medicine (CIRM) Stem Cell Training Program.

Author information

Author notes

  1. Ya-Zhou Wang, Hong Fan, and Yu Ji contribute equally.

Affiliations

  1. Department of Neurobiology and Collaborative Innovation Center for Brain Science, School of Basic Medicine, Fourth Military Medical University, 169 Chang Le Xi Road, Xi’an, 710032, Shaanxi, China

    Ya-Zhou Wang, Hong Fan & Shengxi Wu

  2. Institute for Pediatric Regenerative Medicine of Shriners Hospitals for Children, University of California at Davis, School of Medicine, 2425 Stockton Blvd., Sacramento, CA, 95817, USA

    Ya-Zhou Wang, Yu Ji, Kurt Reynolds, Ran Gu, Qini Gan, Takashi Yamagami, Tianyu Zhao, Salaheddin Hamad, David Pleasure & Chengji J. Zhou

  3. Department of Biochemistry and Molecular Medicine, University of California at Davis, School of Medicine, 2425 Stockton Blvd., Sacramento, CA, 95817, USA

    Yu Ji, Kurt Reynolds, Ran Gu, Kit Lam & Chengji J. Zhou

  4. Division of Neurobiology and Anatomy, Graduate School of Medical and Dental Sciences, Niigata University, Asahimachi, Chuo-ku, Niigata, 951-8510, Japan

    Norihisa Bizen & Hirohide Takebayashi

  5. Department of Cell and Molecular Biology, Tulane University, New Orleans, LA, 70118, USA

    YiPing Chen

Authors
  1. Ya-Zhou Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hong Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yu Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kurt Reynolds
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ran Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Qini Gan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Takashi Yamagami
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tianyu Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Salaheddin Hamad
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Norihisa Bizen
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hirohide Takebayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. YiPing Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Shengxi Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. David Pleasure
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Kit Lam
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Chengji J. Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chengji J. Zhou.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wang, YZ., Fan, H., Ji, Y. et al. Olig2 regulates terminal differentiation and maturation of peripheral olfactory sensory neurons. Cell. Mol. Life Sci. 77, 3597–3609 (2020). https://doi.org/10.1007/s00018-019-03385-x

Download citation

Keywords

  • Basic helix–loop–helix (bHLH) transcription factors
  • Peripheral nervous system (PNS)
  • Tuj1
  • Sox2
  • Fabp7 (Blbp)
  • Dcx