Analysis of the role of keratinocyte Stat3 using the epithelia-specific gene ablation technology.

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We have established keratinocyte-specific Stat3-disrupted mice by using Cre-loxP system under the keratin 5 promoter in order to Investigate the role of Stat3 in signaling required within keratinocytes, since germline ablation of Stat3 gene resulted in early embryonic lethality. Although Stat3-disrupted mice were born normal and no alteration in the skin was found, It was found that wound healing was greatly retarded and the second hair cycle was absent. In vitro migration assay revealed that growth factor-mediated cell migration was markedly impaired in Stat3-disrupted keratinocytes, while their proliferative responses were Intact. These results indicated that Stat3 in keratinocytes was dispensable for skin morphogenesis, but essential for the skin remodeling including wound healing and the progression of the second hair cycle, the processes which required keratinocyte migration. Interestingly, anagen of Stat3- disrupted mice was Induced by topical application of PMA or hair plucking compared to control mice. Furthermore, we found that Stat3-disrupted keratinocytes migrated in vitro upon PKC activation. Given that anagen process required keratinocyte migration, these results suggested that there were at least two distinct pathways for anagen progression based on keratinocyte migration, Stat3-dependent and independent pathways. Interestingly, both signal pathways required PI3K activation. Thus we elucidated signaling pathways and their crosstalks that are Involved in hair cycling using keratinocyte-specific Stat3-disrupted mice.