A Dynamic Model of Keratinocyte Stem Cell Renewal and Differentiation: Role of the p21WAF1/Cip1 and Notch1 Signaling Pathways  Ryuhei Okuyama, Karine LeFort, G. Paolo Dotto  Journal of Investigative Dermatology Symposium Proceedings  Volume 9, Issue 3, Pages 248-252 (September 2004) DOI: 10.1111/j.1087-0024.2004.09308.x Copyright © 2004 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Model of a dynamic equilibrium between keratinocyte populations with different stem cell potential versus commitment to differentiation. Journal of Investigative Dermatology Symposium Proceedings 2004 9, 248-252DOI: (10.1111/j.1087-0024.2004.09308.x) Copyright © 2004 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Hair follicle reconstitution potential of p21+/+versus p21-/- primary keratinocytes. Summary of the results obtained by skin/hair reconstitution assays with primary keratinocytes genetically labeled by infection with a retrovirus transducing the alkaline phosphatase (AP) marker gene (Topley et al, 1999). Experiments were performed with primary keratinocytes derived from either p21+/+ or p21-/- mice of the same genetic background. In each case, mixed populations of approximately 10% infected and 90% uninfected keratinocytes were grafted together with hair-inducing dermal papilla cells. Mice were euthanized 6 weeks after grafting (with reconstituted hair follicles having undergone three hair cycles), and hair follicles in cross section were counted for numbers that consisted of homogeneously AP-positive cells (consistent with being derived from single progenitors) versus numbers of follicles composed of both AP-positive and AP-negative populations (likely to be derived from multiple progenitors). Journal of Investigative Dermatology Symposium Proceedings 2004 9, 248-252DOI: (10.1111/j.1087-0024.2004.09308.x) Copyright © 2004 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Notch signaling in determination of cell fate and stem cell potential. As discussed in the text, there are two possible modes of action of Notch signaling, lateral inhibition (A) and positive reinforcement (B), that are determined by either a negative or positive feedback loop between expression of Notch (N) and its ligands, Delta (D) or Jagged (J). Journal of Investigative Dermatology Symposium Proceedings 2004 9, 248-252DOI: (10.1111/j.1087-0024.2004.09308.x) Copyright © 2004 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Notch1 signaling at the center of the keratinocyte differentiation program. As discussed in the text, Notch1 signaling functions as a direct upstream regulator of p21WAF1/Cip1 expression in mouse keratinocyte differentiation. Notch1 signaling itself is induced with keratinocyte differentiation (A) and, in turn, promotes the exit from the cell cycle and differentiation, through a mechanism, which includes down-modulation of integrin expression (B). Journal of Investigative Dermatology Symposium Proceedings 2004 9, 248-252DOI: (10.1111/j.1087-0024.2004.09308.x) Copyright © 2004 The Society for Investigative Dermatology, Inc Terms and Conditions