Novel insights into the pathways regulating the canine hair cycle and their deregulation in Alopecia X

Alopecia X is a hair cycle arrest disorder in Pomeranians. Histologically, kenogen and telogen hair follicles predominate, whereas anagen follicles are sparse. The induction of anagen relies on the activation of hair follicle stem cells and their subsequent proliferation and differentiation. Stem cell function depends on finely tuned interactions of signaling molecules and transcription factors, which are not well defined in dogs. We performed transcriptome profiling on skin biopsies to analyze altered molecular pathways in alopecia X. Biopsies from five affected and four non-affected Pomeranians were investigated. Differential gene expression revealed a downregulation of key regulator genes of the Wnt (CTNNB1, LEF1, TCF3, WNT10B) and Shh (SHH, GLI1, SMO, PTCH2) pathways, whereas genes of the BMP (BMP4, SMAD2, SMAD7) pathway were deregulated. This is in line with the information gained from mice where BMP signaling is important for stem cell quiescence and Wnt signaling for stem cell activation. We also observed a significant downregulation of the stem cell markers SOX9, LHX2, LGR5, TCF7L1 and GLI1 and upregulation of NFATc1, a quiescence marker, in alopecia X. Moreover, genes relevant for GnRH secretion (KISS1, WNT5a), the melatonin metabolism (CYP1A1, CYP1B1), which influences GnRH secretion and estrogen metabolism as well as genes coding for enzymes directly involved in estrogen metabolism (CYP1A1, CYP1B1, 17ß-HSD14) were deregulated in alopecia X. These findings are in agreement with the so far proposed but not yet proven deregulation of the sex hormone metabolism in this disease.