Abstract
Fibroblast growth factor 5 (FGF5) is a famous dominant inhibitor of anagen phase of hair cycle. Mutations of FGF5 gene result in a longer wool in mice, donkeys, dogs, cats, and even in human eyelashes. Sheep is an important source of wool production. How to improve the production of wool quickly and effectively is an urgent problem to be solved. In this study, we generated five FGF5-knockout Dorper sheep by the CRISPR/Cas9 system. The expression level of FGF5 mRNA in knockout (KO) sheep decreased significantly, and all FGF5 proteins were dysfunctional. The KO sheep displayed a significant increase in fine-wool and active hair-follicle density. The crosstalk between androgen and Wnt/β-catenin signaling downstream of FGF5 gene plays a key role. We established downstream signaling cascades for the first time, including FGF5, FGFR1, androgen, AR, Wnt/β-catenin, Shh/Gli2, c-MYC, and KRTs. These findings further improved the function of FGF5 gene, and provided therapeutic ideas for androgen alopecia.
Highlights
IntroductionHair-follicle development takes place during fetal skin development, and relies on tightly regulated ectodermal–mesodermal interactions
Hair is a primary characteristic of mammals
Is there an association between the increase of wool and active hair-follicle density in Fibroblast growth factor 5 (FGF5) KO sheep and Androgenetic alopecia (AGA)? If so, does crosstalk between AR and Wnt/β-catenin participate in the process of wool and active hair-follicle density in FGF5 KO sheep? Are there any other signaling pathways or other factors that play a role? In this study, we revealed that the crosstalk between androgen and Wnt/β-catenin signaling plays a major role in the increase in wool and active hair-follicle density due to the activation of c-MYC and KRTs associated with inner root sheath (IRS) in FGF5 KO sheep, and the Sonic hedgehog (Shh) pathway is involved in this process as a downstream pathway of Wnt/β-catenin signaling
Summary
Hair-follicle development takes place during fetal skin development, and relies on tightly regulated ectodermal–mesodermal interactions. Mature and actively growing hair follicles eventually become anchored in the subcutis, and periodically regenerate by spontaneously undergoing repetitive cycles. The hair-growth cycle in mammals is composed of three phases: anagen, catagen, and telogen[1,2,3,4]. Subsequent to identification of FGF5 as causative for the angora mouse phenotype, genetic variants in FGF5 have been shown to underlie hair-length regulation in several other species, including cats (Felis catus)[7,8], dogs (Canis lupus familiaris)[9,10], donkeys (Equus africanus asinus)[11], Syrian hamster (Mesocricetus auratus)[12], domestic guinea pigs (Cavia porcellus)[13], and even human (Homo sapiens)[14]
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