037 Role of Stat3 in hair development revealed by the conditional gene targeting

Takeda J. Department of Social and Environmental Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan

Signal transducer and activator of transcription 3 (Stat3) is involved in many signaling pathways for growth factors and cytokines. Its deficiency in mice therefore causes early embryonic lethality, preventing analysis of the functions of the Stat3 gene in adulthood. To circumvent this difficulty and explore the functions of Stat3 in the epidermis, the keratinocytespecific conditional gene targeting using the Cre/loxP system was utilized. Despite functional ablation of Stat3 in the keratinocytes from the mutant mice, no developmental abnormality was observed. However, skin remodeling such as wound healing and second hair cycling was profoundly impaired in the mutant mice. In an in vitro culture system, the migration of keratinocytes from the mutant mice stimulated with various growth factors and cytokines was severely attenuated, which is thought to account for the defect of skin remodeling in the mutant mice. Although the molecular mechanism of Stat3 involvement in keratinocyte migration remains unknown, focal adhesion is enhanced in the mutant, suggesting that Stat3 might be involved in the detachment of keratinocytes from the extracellular matrix rather than the attachment to it. However, the migration by PKC signalling was intact in the mutant mice. These data suggest that Stat3 and PKC pathway were independent for the keratinocyte migration. Wortmannin, an inhibitor of PI3K, impaired the migration of both pathway, implicating PI3K is critically involved in the keratinocyte migration.