Anagen

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EpSc

EpSc

FIGURE 3.7 Diagram showing how Wnt proteins activate quiescent EpSCs of the hair follicle to become transit amplifying (TA) cells. At telogen, Lef-1 acts as a transcriptional repressor in the absence of P-catenin (P-C), which is degraded by GSK-3p. At anagen, Wnt activates the Disheveled 2 (Dvl-2) protein, which inactivates GSK-3p. P-C is stabilized and translocates to the nucleus, where it forms a complex with Lef-1 that stimulates gene transcription characteristic of TA cells.

EpSc

EpSc

FIGURE 3.7 Diagram showing how Wnt proteins activate quiescent EpSCs of the hair follicle to become transit amplifying (TA) cells. At telogen, Lef-1 acts as a transcriptional repressor in the absence of P-catenin (P-C), which is degraded by GSK-3p. At anagen, Wnt activates the Disheveled 2 (Dvl-2) protein, which inactivates GSK-3p. P-C is stabilized and translocates to the nucleus, where it forms a complex with Lef-1 that stimulates gene transcription characteristic of TA cells.

P-catenin to dissociate from APC and complex with Lef-1 to activate genes that release the EpSCs from a quiescent state (figure 3.7). Expression of stabilized P-catenin by deletion or mutation of GSK-3P phosphorylation sites at the N-terminus increased the proportion of P-1 integrin-expressing EpSCs to nearly 90% of the proliferative population in vitro, whereas unstable P-catenin mutants inhibited proliferation of these cells (Zhu and Watt, 1999). Co-transfection of N-terminally truncated (stable) P-catenin and Lef-1 into differentiating mouse keratinocytes caused them to revert to a proliferative state from which they could differentiate into either hair follicles or interfollicular epidermis (Gat et al., 1998).

Mice lacking the retinoblastoma (Rb) proteins p107/ p130, which are required for cell cycling, have fewer hair follicles and display defects in the terminal differentiation of the epidermis. The basal epidermal cells of these mice were found to have increased nuclear accumulation of P-catenin (Ruiz et al., 2004). The increase was due to the increased expression of Frat, a GSK-3P binding protein that prevents degradation of P-catenin. Thus, components of the Wnt pathway in hair follicle bulge cells appear to be linked to cell cycle regulation through the Rb family.

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