1. Cardiovascular Division, Department of Medicine, and
2. Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
3. Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA
4. Present address: Section of Dermatology, Department of Medicine, University of Chicago, 5841 South Maryland Avenue, MC 5067, L504, Chicago, Illinois 60637, USA

Correspondence to: Jonathan A. Epstein¹ Correspondence and requests for materials should be addressed to J.A.E. (Email: epsteinj@mail.med.upenn.edu).

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 melanogenesis^{2, 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 -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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