The G-Protein-Coupled Receptor Kinase 2 Orchestrates Hair Follicle Homeostasis

Tightly regulated cell-cell and cell-niche intercommunications through intertwined signaling networks are involved in maintaining normal hair follicle (HF) homeostasis, cycling, and cell fate determination. However, knowledge of specific mechanisms through which hair loss takes place under pathological situations is needed. Using a keratinocyte-specific knockout mouse model, we uncover that the G-protein-coupled receptor kinase 2 signaling node plays a key role in HF homeostasis. Epidermal G-protein-coupled receptor kinase 2 ablation causes alterations during anagen induction, giving rise to abnormal cyst-like structures. HF-linked cysts display aberrant growth and differentiation patterns as well as lineage infidelity, displaying features of abortive HFs unable to fully acquire canonical hallmarks. Cysts triggered by G-protein-coupled receptor kinase 2 deletion displace the dermal papilla away from the bulge and promote irreversible changes in HF stem cell architecture, leading to bulge destruction and hair loss. Our data provide unforeseen roles of G-protein-coupled receptor kinase 2 in epidermal physiology and uncover the mechanisms linking dystrophic follicular cysts formation with hair loss, with potential connections to pathogenic processes operating in immune-mediated alopecias.