Cutaneous gain-of-function mutation of LRIG3 leads to alopecia by upregulation of ERBB, PI3K/AKT, NOTCH1 signaling pathways

Homeostasis of the skin relies on meticulous regulation of integrated pathways. Within this network, ERBB receptors are of great importance in controlling the proliferation, differentiation, and survival of epidermal and hair follicle (HF) keratinocytes as well as sebaceous glands (SGs) in the skin. Consequently, leucine-rich repeats and immunoglobulin-like domains (LRIG) protein family comprising LRIG1, LRIG2, and LRIG3 as one of the fundamental regulators of ERBB receptors plays a pivotal role in tissue development and homeostasis. The function of LRIGs in maintaining skin homeostasis is primarily understood due to the most extensively studied member, LRIG1. However, the role of LRIG3, the last member of this protein family in the skin, is unknown. While its function has been demonstrated in development and maintenance of the homeostasis of various tissues such as inner ear and neural crest morphogenesis via modulating NOTCH and fibroblast growth factor signaling pathways, respectively. Here, we provided the first insights into how Lrig3 overexpression in mouse skin, using the Tet-Off-System, influences cutaneous homeostasis. After overcoming the prenatal lethality of Lrig3 overexpression and obtaining an adequate number of skin-specific Lrig3 transgenic (Lrig3-TG) mice, the first clinical feature was hair loss in these mice. Subsequent investigations revealed extensive changes in the skin protein profile, particularly in keratinocyte differentiation as well as HF and SG markers, along with altered signaling pathways governing HF development. Our study implies up-regulation of the components of ERBB, NOTCH, PI3K/AKT pathways in the skin of Lrig3-TG mice, suggesting a potential role of the Lrig3 in maintaining skin balance.