Journal Mobile Options
Table of Contents
Vol. 25, No. 1, 2003
Issue release date: January–February (July 2003)
Dev Neurosci 2003;25:50–64

Notch1 and Numb Genes Are Inversely Expressed as Oligodendrocytes Differentiate

Givogri M.I. · Schonmann V. · Cole R. · de Vellis J. · Bongarzone E.R.
aLaboratory for Gene Therapy of Neurodegenerative Disorders, San Raffaele Telethon Institute for Gene Therapy, Milano, Italy; bDevelopmental Biology and cNeurobiology Groups, Mental Retardation Research Center, University of California, Los Angeles, Calif., USA

Individual Users: Register with Karger Login Information

Please create your User ID & Password

Contact Information

I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in


The Notch1 pathway plays a fundamental role during the establishment of cell fates in the central nervous system (CNS) by regulating neural cell differentiation. In oligodendrocytes (OLs), Notch1 activity prevents these cells from becoming terminally mature, thereby influencing CNS myelination. Little is known of how OLs regulate the expression of this receptor at the gene level or if OLs have mechanisms to control the level of intracellular activity of the Notch1 pathway. In this study, we have found that Notch1 gene expression was higher in proliferative OL progenitor cells (OPCs) and was reduced when cells were forced to withdraw from the cell cycle and became mature, indicating that Notch1 gene expression is developmentally regulated in OLs. We observed that the blockade of terminal differentiation of OPCs by incubation with Delta1, an activator of Notch1, was a dominant process and OL-differentiating signals such as thyroid hormone could not overcome this inhibition in culture. This suggests that a downregulation of the Notch1 pathway might be required to allow OPCs to enter terminal differentiation. We also provide evidence that OPCs and OLs express the Numb gene, a known negative regulator of Notch1 activity. In vivo, Numb was found in postnatal OLs from cerebellar and cerebral white matter. In vitro, Numb expression showed to be inversely correlated to that of Notch1, with higher levels of Numb proteins in mature OLs, in association with myelin-like membranes.

Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.


  1. Baron M, Aslam H, Flasza M, Fostier M, Higgs JE, Mazaleyrat SL, Wilkin MB (2002): Multiple levels of Notch signal regulation (review). Mol Membr Biol 19:27–38.
  2. Barres BA, Hart IK, Coles HS, Burne JF, Voyvodic JT, Richardson WD, Raff MC (1992): Cell death and control of cell survival in the oligodendrocyte lineage. Cell 70:31–46.
  3. Barres BA, Lazar MA, Raff MC (1994a): A novel role for thyroid hormone, glucocorticoids and retinoic acid in timing oligodendrocyte development. Development 120:1097–108.
  4. Barres BA, Raff MC, Gaese F, Bartke I, Dechant G, Barde YA (1994b): A crucial role for neurotrophin-3 in oligodendrocyte development. Nature 367:371–375.
  5. Barres BA, Schmid R, Sendtner M, Raff MC (1993): Multiple extracellular signals are required for long-term oligodendrocyte survival. Development 118:283–295.
  6. Bongarzone ER, Byravan S, Givogri MI, Schonmann V, Campagnoni AT (2000): Platelet-derived growth factor and basic fibroblast growth factor regulate cell proliferation and the expression of notch-1 receptor in a new oligodendrocyte cell line. J Neurosci Res 62:319–328.
  7. Bongarzone ER, Foster LM, Byravan S, Verity AN, Landry CF, Schonmann VV, Amur-Umarjee S, Campagnoni AT (1996): Conditionally immortalized neural cell lines: Potential models for the study of neural cell function. Methods 10:489–500.
  8. Bongarzone ER, Givogri MI (2002): Myelinating glial cells in the central nervous system. Rec Res Dev Neurochem 5:21–38.
  9. Casaccia-Bonnefil O, Tikoo R, Kiyokawa H, Friedrich V, Chao M, Koff A (1997): Oligodendrocyte precursor differentiation is perturbed in the absence of the cyclin-dependent kinase inhibitor p27kip1. Genes Dev 11:2335–2346.
  10. Cayouette M, Whitmore AV, Jeffery G, Raff M (2001): Asymmetric segregation of Numb in retinal development and the influence of the pigmented epithelium. J Neurosci 21:5643–5651.
  11. Cole R, de Vellis J (2001): Preparation of astrocyte, oligodendrocyte and microglia cultures from primary rat cerebral cultures; in: Protocols for Neural Cell Culture, ed 3. Clifton, Humana Press, pp 117–128.
  12. De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, Schroeder EH, Schrijvers V, Wolfe MS, Ray WJ, Goate A, Kopan R (1999): A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain. Nature 398:518–521.
  13. Durand B, Gao FB, Raff M (1997): Accumulation of the cyclin-dependent kinase inhibitor p27kip1 and the timing of oligodendrocyte differentiation. EMBO J 16:1139–1148.
  14. Ellison JA, Scully SA, de Vellis J (1996): Evidence for neuronal regulation of oligodendrocyte development: Cellular localization of platelet-derived growth factor alpha receptor and A-chain mRNA during cerebral cortex development in the rat. J Neurosci Res 45:28–39.
  15. Escobar Cabrera OE, Bongarzone ER, Soto EF, Pasquini JM (1994): Single intracerebral injection of apotransferrin in young rats induces increased myelination. Dev Neurosci 16:248–254.
  16. Espinosa de los Monteros A, Kumar S, Zhao P, Huang CJ, Nazarian R, Pan T, Scully S, Chang R, de Vellis J (1999): Transferrin is an essential factor for myelination. Neurochem Res 24:235–248.
  17. Fok-Seang J, Miller RH (1994): Distribution and differentiation of A2B5+ glial precursors in the developing rat spinal cord. J Neurosci Res 37:219–235.
  18. Fortini ME, Artavanis-Tsakonas S (1994): The suppressor of Hairless protein participates in Notch receptor signaling. Cell 79:273–282.
  19. Fruttiger M, Calver AR, Richardson WD (2000): Platelet-derived growth factor is constitutively secreted from neuronal cell bodies but not from axons. Curr Biol 10:1283–1286.

    External Resources

  20. Gao FB, Apperly J, Raff M (1998): Cell-intrinsic timers and thyroid hormone regulate the probability of cell-cycle withdrawal and differentiation of oligodendrocyte precursor cells. Dev Biol 197:54–66.
  21. Gard AL, Pfeiffer SE (1990): Two proliferative stages of the oligodendrocyte lineage (A2B5+O4– and O4+GalC–) under different mitogenic control. Neuron 5:615–625.
  22. Gard AL, Pfeiffer SE (1993): Glial cell mitogens bFGF and PDGF differentially regulate development of O4+GalC– oligodendrocyte progenitors. Dev Biol 159:618–630.
  23. Genoud S, Lappe-Siefke C, Goebbels S, Radtke F, Aguet M, Scherer SS, Suter U, Nave KA, Mantei N (2002): Notch1 control of oligodendrocyte differentiation in the spinal cord. J Cell Biol 158:709–718.
  24. Givogri MI, Costa RM, Schonmann V, Silva AJ, Campagnoni AT, Bongarzone ER (2002): Central nervous system myelination in mice with deficient expression of Notch1 receptor. J Neurosci Res 67:309–320.
  25. Guo M, Jan LY, Jan YN (1996): Control of daughter cell fates during asymmetric division: Interaction of Numb and Notch. Neuron 17:27–41.
  26. Jarriault S, Brou C, Logeat F, Schroeter E, Kapan R, Israel A (1995): Signaling downstream if activated mammalian Notch. Nature 377:355–358.
  27. John GR, Shankar SL, Zagardo B, Massimi A, Lee S, Raine CS, Brosnan CF (2002): Multiple sclerosis: Re-expression of a developmental pathway that restricts oligodendrocyte maturation. Nat Med 8:1115–1121.
  28. Kahn MA, Kumar S, Liebl D, Chang R, Parada LF, De Vellis J (1999): Mice lacking NT-3, and its receptor TrkC, exhibit profound deficiencies in CNS glial cells. Glia 26:153–165.
  29. Kato H, Taniguchi Y, Kurooka H, Minoguchi S, Sakai T, Nomura-Okazaki S, Tamura K, Honjo T (1997): Involvement of RBP-J in biological functions of mouse Notch1 and its derivatives. Development 124:4133–4141.
  30. Knoblich JA, Jan LY, Jan YN (1995): Asymmetric segregation of Numb and Prospero during cell division. Nature 377:624–627.
  31. Kondo T, Raff M (2000): Basic helix-loop-helix proteins and the timing of oligodendrocyte differentiation. Development 127:2989–2998.
  32. McKinnon RD, Matsui T, Dubois-Dalcq M, Aaronson SA (1990): FGF modulates the PDGF-driven pathway of oligodendrocyte development. Neuron 5:603–614.
  33. Miller RH (1996): Oligodendrocyte origins. Trends Neurosci 19:92–96.
  34. Miller RH, Hayes JE, Dyer KL, Sussman CR (1999): Mechanisms of oligodendrocyte commitment in the vertebrate CNS. Int J Dev Neurosci 17:753–763.
  35. Miller RH, Payne J, Milner L, Zhang H, Orentas DM (1997): Spinal cord oligodendrocytes develop from a limited number of migratory highly proliferative precursors. J Neurosci Res 50:157–168.
  36. Morrison SJ, Perez SE, Qiao Z, Verdi JM, Hicks C, Weinmaster G, Anderson DJ (2000): Transient Notch activation initiates an irreversible switch from neurogenesis to gliogenesis by neural crest stem cells. Cell 101:499–510.
  37. Mumm S, Schroeter EH, Saxena MT, Griesemer A, Tian X, Pan DJ, Ray WJ, Kopan R (2000): A ligand-induced extracellular cleavage regulates gamma-secretase like proteolytic activation of Notch1. Mol Cell 5:197–206.
  38. Noble M, Murray K (1984): Purified astrocytes promote the in vitro division of a bipotential glial progenitor cell. EMBO J 3:2243–2247.
  39. Noble M, Murray K, Stroobant P, Waterfield MD, Riddle P (1988): Platelet-derived growth factor promotes division and motility and inhibits premature differentiation of the oligodendrocyte/type-2 astrocyte progenitor cell. Nature 333:560–562.
  40. Raff MC, Lillien LE, Richardson WD, Burne JF, Noble MD (1988): Platelet-derived growth factor from astrocytes drives the clock that times oligodendrocyte development in culture. Nature 333:562–565.
  41. Raff MC, Miller RH, Noble M (1983): A glial progenitor cell that develops in vitro into an astrocyte or an oligodendrocyte depending on culture medium. Nature 303:390–396.
  42. Richardson WD, Pringle N, Mosley MJ, Westermark B, Dubois-Dalcq M (1988): A role for platelet-derived growth factor in normal gliogenesis in the central nervous system. Cell 53:309–319.
  43. Struhl G, Greenwald I (1999): Presenilin is required for activity and nuclear access of Notch in Drosophila. Nature 398:522–524.
  44. Struhl G, Greenwald I (2001): Presenilin-mediated transmembrane cleavage is required for Notch signal transduction in Drosophila. Proc Natl Acad Sci USA 98:229–234.
  45. Wakamatsu Y, Maynard TM, Jones SU, Weston JA (1999): NUMB localizes in the basal cortex of mitotic avian neuroepithelial cells and modulates neuronal differentiation by binding to NOTCH-1. Neuron 23:71–81.
  46. Wang S, Sdrulla AD, diSibio G, Bush G, Nofziger D, Hicks C, Weinmaster G, Barres B (1998): Notch receptor activation inhibits oligodendrocyte differentiation. Neuron 21:63–75.
  47. Warrington AE, Pfeiffer SE (1992): Proliferation and differentiation of O4+ oligodendrocytes in postnatal rat cerebellum: Analysis in unfixed tissue slices using anti-glycolipid antibodies. J Neurosci Res 33:338–353.
  48. Wolswijk G, Noble M (1992): Cooperation between PDGF and FGF converts slowly dividing O-2Aadult progenitor cells to rapidly dividing cells with characteristics of O-2Aperinatal progenitor cells. J Cell Biol 118:889–900.
  49. Wolswijk G, Riddle PN, Noble M (1991): Platelet-derived growth factor is mitogenic for O-2A adult progenitor cells. Glia 4:495–503.
  50. Zhong W, Jiang MM, Schonemann MD, Meneses JJ, Pedersen RA, Jan LY, Jan YN (2000): Mouse numb is an essential gene involved in cortical neurogenesis. Proc Natl Acad Sci USA 97:6844–6849.
  51. Zhong W, Jiang MM, Weinmaster G, Jan LY, Jan YN (1997): Differential expression of mammalian Numb, Numblike and Notch1 suggests distinct roles during mouse cortical neurogenesis. Development 124:1887–1897.

Pay-per-View Options
Direct payment This item at the regular price: USD 9.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 8.00