Receptor activator of NF-κB (RANK), known for controlling bone mass, has been recognized for its role in epithelial cell activation of the mammary gland. Because bone and the epidermo-pilosebaceous unit of the skin share a lifelong renewal activity where similar molecular players operate, and because mammary glands and hair follicles are both skin appendages, we have addressed the function of RANK in the hair follicle and the epidermis. Here, we show that mice deficient in RANK ligand (RANKL) are unable to initiate a new growth phase of the hair cycle and display arrested epidermal homeostasis. However, transgenic mice overexpressing RANK in the hair follicle or administration of recombinant RANKL both activate the hair cycle and epidermal growth. RANK is expressed by the hair follicle germ and bulge stem cells and the epidermal basal cells, cell types implicated in the renewal of the epidermopilosebaceous unit. RANK signaling is dispensable for the formation of the stem cell compartment and the inductive hair follicle mesenchyme, and the hair cycle can be rescued by Rankl knockout skin transplantation onto nude mice. RANKL is actively transcribed by the hair follicle at initiation of its growth phase, providing a mechanism for stem cell RANK engagement and hair-cycle entry. Thus, RANK-RANKL regulates hair renewal and epidermal homeostasis and provides a link between these two activities.R eceptor activator of NF-κB (RANK), a member of the TNF receptor family (TNFRSF11a), was originally identified as a regulator of bone density. Mice deficient in Rank or Rankl display increased bone density owing to reduced osteoclast formation, but the loss of the RANK ligand (RANKL) decoy receptor osteoprotegerin (OPG) results in lower bone mass because of unchecked RANK activation (1, 2).RANK has emerged as an important player in epithelial cell growth and differentiation. It is required for the formation of lactating mammary glands (3, 4), thymic medullary epithelial cells (5), and intestinal microfold cells (6) and has been implicated in the growth and metastasis of prostate (7) and mammary epithelial cancers (8, 9). Thus, RANK affects a great variety of epithelial cells of different organs. The skin is the largest epithelial surface, and its epidermo-pilosebaceous unit comprises the interfollicular epidermis (IFE), the hair follicle (HF), and the sebaceous gland. The HF has the particularity of undergoing cycles of growth (anagen), regression (catagen), and relative quiescence (telogen) (10), making it an excellent system for studying epidermal (stem) cells and organ remodeling (11)(12)(13)(14). Each HF is composed of a permanent upper portion, which includes the sebaceous gland and the bulge region, and a temporary lower cycling portion. The local balance of hair growth stimulators and inhibitors is critical for initiation of new hair growth (15-17). Intriguingly, many of these molecular players also operate in bone development and remodeling (e.g., members of the TGF-β superfamily and their antagonists, parathyroid hormo...

RANK and its ligand RANKL play important roles in the development and regulation of the immune system. We show that mice transgenic for Rank in hair follicles display massive postnatal growth of skin-draining lymph nodes. The proportions of hematopoietic and nonhematopoietic stromal cells and their organization are maintained, with the exception of an increase in B cell follicles. The hematopoietic cells are not activated and respond to immunization by foreign Ag and adjuvant. We demonstrate that soluble RANKL is overproduced from the transgenic hair follicles and that its neutralization normalizes lymph node size, inclusive area, and numbers of B cell follicles. Reticular fibroblastic and vascular stromal cells, important for secondary lymphoid organ formation and organization, express RANK and undergo hyperproliferation, which is abrogated by RANKL neutralization. In addition, they express higher levels of CXCL13 and CCL19 chemokines, as well as MAdCAM-1 and VCAM-1 cell-adhesion molecules. These findings highlight the importance of tissue-derived cues for secondary lymphoid organ homeostasis and identify RANKL as a key molecule for controlling the plasticity of the immune system.