miR-29a/b1 Inhibits Hair Follicle Stem Cell Lineage Progression by Spatiotemporally Suppressing WNT and BMP Signaling

Summary: Hair follicle stem cells (HFSCs) and subsequent generations of matrix progeny make lineage choices by responding to spatiotemporal signals; however, the cues driving that specification are not well understood. Here, we demonstrate that the dynamics of microRNA (miR)-29 expression are inversely proportional to HFSC lineage progression. Furthermore, we show that sustained miR-29a/b1 overexpression in anagen or telogen in mice causes a short-hair phenotype and eventual hair loss by inhibiting the proliferation of HFSCs and matrix cells and likely preventing their differentiation. Conversely, in a loss-of-function in vivo model, miR-29a/b1 deficiency accelerates HFSC lineage progression in telogen. Mechanistically, miR-29a/b1 blocks HFSC lineage specification by spatiotemporally targeting Ctnnb1, Lrp6, Bmpr1a, and Ccna2. We further show that skin-specific Lrp6 or Bmpr1a ablation partially accounts for the short-hair phenotype. Overall, these synergistic targets reveal miR-29a/b1 as a high-fidelity antagonist of HFSC lineage progression and a potential therapeutic target for hair loss. : By using miR-29a/b1 gain- and loss-of-function mouse models, Ge et al. reveal that miR-29a/b1 suppresses lineage progression of hair follicle stem cells and matrix cells by spatiotemporally synergistic targets, Lrp6, Ctnnb1, and Bmpr1a. Keywords: miR-29a/b1, HFSC lineage progression, matrix, proliferation and differentiation, short hair, spatiotemporal targets, Lrp6, Bmpr1a, WNT pathway, BMP pathway