Ephrin-A3 not only increases the density of hair follicles but also accelerates anagen development in neonatal mice.

BACKGROUND: Ephrins are cell-membrane-bound ligands for Eph receptor tyrosine kinases (Eph). Although ephrins are known to regulate a variety of developmental processes, little is known of their role in hair development. Previously, we studied the gene expression of dermal papilla cells from androgenetic alopecia and found that ephrin-A3 was significantly down-regulated. OBJECTIVE: To characterize the expression of ephrin-A3 in the hair cycle and evaluate the effect of ephrin-A3 on hair growth. METHODS: We investigated gene expression and protein expression of each ephrin-As and EphAs in the skin of neonatal mice through the first and second hair cycle using quantitative PCR and immunohistochemical analysis, respectively. We also injected ephrin-A3 protein into the skin of neonatal mice and demonstrated the effect of ephrin-A3 on hair follicle development. RESULTS: Expression of ephrin-A3 revealed a rapid increase at the beginning of the anagen phase, a peak during the mid-anagen, and a rapid fading during the telogen phase. In addition, we found ephrin-A3 protein was expressed in the developing hair follicles with a characteristic spatiotemporal localization. Furthermore, injection of ephrin-A3 into the skin of neonatal mice markedly accelerated the differentiation process of hair follicles. In addition, injection of ephrin-A3 unexpectedly increased the number of hair follicles. CONCLUSION: These findings demonstrated that ephrin-A3 not only accelerates anagen development but also increases the density of hair follicles, and also suggested that an ephrin-A-EphA signal pathway is closely involved in hair follicle development.

Expression profile of Eph receptors and ephrin ligands in human skin and downregulation of EphA1 in nonmelanoma skin cancer.

Eph receptors and ephrin ligands represent the largest family of receptor tyrosine kinases. Beyond their well-defined meaning in developmental processes, these molecules also have important functions in adult human tissues and cancer. However, the Eph/ephrin expression profile in human skin is only marginally studied. We therefore investigated the mRNA expression of 21 Eph receptors and ephrin ligands in adult human skin in comparison to 13 other adult human tissues using quantitative real-time RT-PCR. In addition, immunohistochemistry was established for some members (EphA1, EphA2 and EphA7) to confirm the results of the RT-PCR and to identify the expressing cells in the skin. We found all investigated family members expressed in human skin, but at highly varying levels. EphA1, EphB3 and ephrin-A3 turned out to be most prominently expressed in skin compared to other adult human tissues. EphA1 was exclusively expressed in the epidermis. We therefore investigated the expression of EphA1 in nonmelanoma skin cancers derived from the epidermis (56 basal cell carcinomas and 32 squamous cell carcinomas). As demonstrated by immunohistochemistry, both skin cancers displayed a significant downregulation of EphA1 compared to the normal epidermis. In squamous cell carcinoma, the EphA1 downregulation was associated with increased tumor thickness, although this was not significant. Our results indicate that Eph receptors and ephrin ligands are widely expressed in the adult human skin, particularly in the epidermis, and may play an important role in skin homeostasis. EphA1 seems to be a marker of the differentiated normal epidermis and its downregulation in nonmelanoma skin cancer may contribute to carcinogenesis of these very frequent human tumors. EphA1 represents a new potential prognostic marker and therapeutic target in nonmelanoma skin cancer.