Thesis Title:
A transgenic mouse model to study the role of epidermal growth factor (EGF) in hair and skin development.
The hair growth cycle consists of three stages known as the anagen (growing), catagen (involution) and telogen (resting) phases. This cyclical growth of hair is regulated by a diversity of growth factors including members of the epidermal growth factor (EGF) family. Both EGF and TGF alpha bind the EGF receptor (erbB1). Null mutations in TGF alpha and a point mutation in EGF receptors result in wavy hair and curly whiskers in mice. Here we show that continuous expression of EGF in hair follicle causes alopecia. Whereas normal expression of both EGF and its receptors are down-regulated after the anagen phase, continuous expression of EGF in hair follicles of transgenic mice arrested follicular development in the anagen phase. No structural abnormality is observed in prenatal and perinatal stages in transgenic mice. However, hair follicles in transgenic mice remained in the anagen phase when the hair follicles in littermates have already completed the first hair cycle. Besides disrupting the normal hair cycle, EGF causes thinner hair growth. We further showed that EGF signals through erbB1/erbB2 heterodimers in skin by immunoprecipitation and western blotting. In addition, topical application of tyrphostin AG1478 or AG 825, a selective inhibitor of erbB1 and erbB2 tyrosine kinase activity respectively, completely inhibited new hair growth in wild type mice but not in transgenic mice. When the transgenic mice were crossed with waved-2 mice, which possess a much lower activity of EGF receptors, the alopecia phenotype was completely rescued in the offspring, further suggesting that upregulation of EGF receptor signaling leads to alopeica. Taken together, these data suggest that EGF receptor signaling is indispensable for initiation of hair growth and that continuous expression of EGF arrests entry into the catagen phase. We therefore propose that EGF functions as a biologic switch which is turned on and off in hair follicles at the beginning and end of the anagen phase of the hair cycle respectively, guarding the precise entry and exit of anagen phase in the hair cycle. |
