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Pax3 functions at a nodal point in melanocyte stem cell differentiation

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.

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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.

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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.

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Correspondence to Jonathan A. Epstein.

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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)

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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

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