Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Pax3 functions at a nodal point in melanocyte stem cell differentiation

Nature volume 433, pages 884–887 (2005)Cite this article

Abstract

Most stem cells are not totipotent. Instead, they are partially committed but remain undifferentiated. Upon appropriate stimulation they are capable of regenerating mature cell types1. Little is known about the genetic programmes that maintain the undifferentiated phenotype of lineage-restricted stem cells. Here we describe the molecular details of a nodal point in adult melanocyte stem cell differentiation in which Pax3 simultaneously functions to initiate a melanogenic cascade while acting downstream to prevent terminal differentiation. Pax3 activates expression of Mitf, a transcription factor critical for melanogenesis2,3, while at the same time it competes with Mitf for occupancy of an enhancer required for expression of dopachrome tautomerase, an enzyme that functions in melanin synthesis4. Pax3-expressing melanoblasts are thus committed but undifferentiated until Pax3-mediated repression is relieved by activated β-catenin. Thus, a stem cell transcription factor can both determine cell fate and simultaneously maintain an undifferentiated state, leaving a cell poised to differentiate in response to external stimuli.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Pax3 is expressed in mature hair follicles.
Figure 2: Pax3 and Mitf regulate Dct and compete for enhancer occupancy.
Figure 3: Activated β-catenin modulates Pax3 activity.
Figure 4: Dct expression requires activated β-catenin.

Similar content being viewed by others

References

  1. Fuchs, E., Tumbar, T. & Guasch, G. Socializing with the neighbors: stem cells and their niche. Cell 116, 769–778 (2004)

    Article  CAS  Google Scholar 

  2. Potterf, S. B., Furumura, M., Dunn, K. J., Arnheiter, H. & Pavan, W. J. Transcription factor hierarchy in Waardenburg syndrome: regulation of MITF expression by SOX10 and PAX3. Hum. Genet. 107, 1–6 (2000)

    Article  CAS  Google Scholar 

  3. Watanabe, A., Takeda, K., Ploplis, B. & Tachibana, M. Epistatic relationship between Waardenburg syndrome genes MITF and PAX3. Nature Genet. 18, 283–286 (1998)

    Article  CAS  Google Scholar 

  4. Yasumoto, K. et al. Microphthalmia-associated transcription factor interacts with LEF-1, a mediator of Wnt signaling. EMBO J. 21, 2703–2714 (2002)

    Article  CAS  Google Scholar 

  5. Steel, K. P., Davidson, D. R. & Jackson, I. J. TRP-2/DT, a new early melanoblast marker, shows that steel growth factor (c-kit ligand) is a survival factor. Development 115, 1111–1119 (1992)

    CAS  PubMed  Google Scholar 

  6. Tsukamoto, K., Jackson, I. J., Urabe, K., Montague, P. M. & Hearing, V. J. A second tyrosinase-related protein, TRP-2, is a melanogenic enzyme termed DOPAchrome tautomerase. EMBO J. 11, 519–526 (1992)

    Article  CAS  Google Scholar 

  7. Nishimura, E. K. et al. Dominant role of the niche in melanocyte stem-cell fate determination. Nature 416, 854–860 (2002)

    Article  ADS  CAS  Google Scholar 

  8. Widlund, H. R. & Fisher, D. E. Microphthalamia-associated transcription factor: a critical regulator of pigment cell development and survival. Oncogene 22, 3035–3041 (2003)

    Article  CAS  Google Scholar 

  9. Kuhlbrodt, K., Herbarth, B., Sock, E., Hermans-Borgmeyer, I. & Wegner, M. Sox10, a novel transcriptional modulator in glial cells. J. Neurosci. 18, 237–250 (1998)

    Article  CAS  Google Scholar 

  10. Bondurand, N. et al. Interaction among SOX10, PAX3 and MITF, three genes altered in Waardenburg syndrome. Hum. Mol. Genet. 9, 1907–1917 (2000)

    Article  CAS  Google Scholar 

  11. Bertolotto, C. et al. Microphthalmia gene product as a signal transducer in cAMP-induced differentiation of melanocytes. J. Cell Biol. 142, 827–835 (1998)

    Article  CAS  Google Scholar 

  12. Aksan, I. & Goding, C. R. Targeting the microphthalmia basic helix-loop-helix-leucine zipper transcription factor to a subset of E-box elements in vitro and in vivo . Mol. Cell. Biol. 18, 6930–6938 (1998)

    Article  CAS  Google Scholar 

  13. Jin, Z. X. et al. Lymphoid enhancer-binding factor-1 binds and activates the recombination-activating gene-2 promoter together with c-Myb and Pax-5 in immature B cells. J. Immunol. 169, 3783–3792 (2002)

    Article  CAS  Google Scholar 

  14. Eberhard, D., Jimenez, G., Heavey, B. & Busslinger, M. Transcriptional repression by Pax5 (BSAP) through interaction with corepressors of the Groucho family. EMBO J. 19, 2292–2303 (2000)

    Article  CAS  Google Scholar 

  15. Cai, Y., Brophy, P. D., Levitan, I., Stifani, S. & Dressler, G. R. Groucho suppresses Pax2 transactivation by inhibition of JNK-mediated phosphorylation. EMBO J. 22, 5522–5529 (2003)

    Article  CAS  Google Scholar 

  16. Roose, J. et al. The Xenopus Wnt effector XTcf-3 interacts with Groucho-related transcriptional repressors. Nature 395, 608–612 (1998)

    Article  ADS  CAS  Google Scholar 

  17. Behrens, J. et al. Functional interaction of beta-catenin with the transcription factor LEF-1. Nature 382, 638–642 (1996)

    Article  ADS  CAS  Google Scholar 

  18. DasGupta, R. & Fuchs, E. Multiple roles for activated LEF/TCF transcription complexes during hair follicle development and differentiation. Development 126, 4557–4568 (1999)

    CAS  Google Scholar 

  19. Chu, E. Y. et al. Canonical WNT signaling promotes mammary placode development and is essential for initiation of mammary gland morphogenesis. Development 131, 4819–4829 (2004)

    Article  CAS  Google Scholar 

  20. Andl, T., Reddy, S. T., Gaddapara, T. & Millar, S. E. WNT signals are required for the initiation of hair follicle development. Dev. Cell 2, 643–653 (2002)

    Article  CAS  Google Scholar 

  21. Ikeya, M., Lee, S. M., Johnson, J. E., McMahon, A. P. & Takada, S. Wnt signalling required for expansion of neural crest and CNS progenitors. Nature 389, 966–970 (1997)

    Article  ADS  CAS  Google Scholar 

  22. Lee, H. Y. et al. Instructive role of Wnt/beta-catenin in sensory fate specification in neural crest stem cells. Science 303, 1020–1023 (2004)

    Article  ADS  CAS  Google Scholar 

  23. Garcia-Castro, M. I., Marcelle, C. & Bronner-Fraser, M. Ectodermal Wnt function as a neural crest inducer. Science 297, 848–851 (2002)

    ADS  CAS  PubMed  Google Scholar 

  24. Huelsken, J., Vogel, R., Erdmann, B., Cotsarelis, G. & Birchmeier, W. Beta-catenin controls hair follicle morphogenesis and stem cell differentiation in the skin. Cell 105, 533–545 (2001)

    Article  CAS  Google Scholar 

  25. Hari, L. et al. Lineage-specific requirements of beta-catenin in neural crest development. J. Cell Biol. 159, 867–880 (2002)

    Article  CAS  Google Scholar 

  26. Brault, V. et al. Inactivation of the beta-catenin gene by Wnt1-Cre-mediated deletion results in dramatic brain malformation and failure of craniofacial development. Development 128, 1253–1264 (2001)

    CAS  PubMed  Google Scholar 

  27. Kim, J., Lo, L., Dormand, E. & Anderson, D. J. SOX10 maintains multipotency and inhibits neuronal differentiation of neural crest stem cells. Neuron 38, 17–31 (2003)

    Article  CAS  Google Scholar 

  28. Ashery-Padan, R. & Gruss, P. Pax6 lights-up the way for eye development. Curr. Opin. Cell Biol. 13, 706–714 (2001)

    Article  CAS  Google Scholar 

  29. Marquardt, T. et al. Pax6 is required for the multipotent state of retinal progenitor cells. Cell 105, 43–55 (2001)

    Article  CAS  Google Scholar 

  30. Nutt, S. L., Heavey, B., Rolink, A. G. & Busslinger, M. Commitment to the B-lymphoid lineage depends on the transcription factor Pax5. Nature 401, 556–562 (1999)

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We thank A. Glick for K5-rtTA mice, M. Shin and E. Morrisey for mice and scientific advice, and T. Andl, A. Souabni, C. Lobe, W. Birchmeier, G. Oliver, T. Force and P. Hamel for reagents. This work was supported by grants from the NIH to S.E.M. and J.A.E.

Author information

Author notes

  1. Deborah Lang

    Present address: Section of Dermatology, Department of Medicine, University of Chicago, 5841 South Maryland Avenue, MC 5067, L504, Chicago, Illinois, 60637, USA

Authors and Affiliations

  1. Cardiovascular Division, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, USA

    Deborah Lang, Min Min Lu, Li Huang, Kurt A. Engleka, Maozhen Zhang & Jonathan A. Epstein

  2. Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, USA

    Emily Y. Chu & Sarah E. Millar

  3. Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, 10461, USA

    Shari Lipner & Arthur Skoultchi

Authors
  1. Deborah Lang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Min Min Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Li Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kurt A. Engleka
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maozhen Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Emily Y. Chu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shari Lipner
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Arthur Skoultchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sarah E. Millar
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jonathan A. Epstein
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jonathan A. Epstein.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Methods

Detailed experimental methods and references. (DOC 43 kb)

Supplementary Figure S1

Additional data regarding the regulation of DCT by Pax3, Sox10 and MITF. (GIF 101 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lang, D., Lu, M., Huang, L. et al. Pax3 functions at a nodal point in melanocyte stem cell differentiation. Nature 433, 884–887 (2005). https://doi.org/10.1038/nature03292

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature03292

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing