Pax3 functions at a nodal point in melanocyte stem cell differentiation.
Most stem cells are not totipotent. Instead, they are partially committed but remain undifferentiated. Upon appropriate stimulation they are capable of regenerating mature cell types. 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, 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 synthesis. Pax3-expressing melanoblasts are thus committed but undifferentiated until Pax3-mediated repression is relieved by activated beta-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.
Lang
Deborah
D
Cardiovascular Division, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Lu
Min Min
MM
Huang
Li
L
Engleka
Kurt A
KA
Zhang
Maozhen
M
Chu
Emily Y
EY
Lipner
Shari
S
Skoultchi
Arthur
A
Millar
Sarah E
SE
Epstein
Jonathan A
JA
D000375:Aging / Q000502:physiology; D000818:Animals; D001483:Base Sequence; D001667:Binding, Competitive; D002454:Cell Differentiation; D002460:Cell Line; D019070:Cell Lineage; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005786:Gene Expression Regulation; D018859:Hair Follicle / Q000378:metabolism; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics; D008544:Melanocytes / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor; D008969:Molecular Sequence Data; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D017384:Sequence Deletion / Q000235:genetics; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D051176:beta Catenin
C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin; C068686:Pax3 protein, mouse; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase