Dynamic expression of Runx1 in skin affects hair structure

Abstract

The three mammalian Runx transcription factors, some of which are known to be involved in human genetic diseases and cancer, are pivotal players in embryo development and function as key regulators of cell fate determination and organogenesis. Here, we report the expression of Runx1 during the development of hair and other skin appendages in the mouse and describe the effect of Runx1 on the structural hair output. In hair follicles, where the three Runx proteins are expressed, Runx1 expression is most prominent in both mesenchymal and epithelial compartments. The epithelial expression includes the hair keratin forming layers of the hair shaft and the bulge, where interestingly, Runx1 is co-expressed with keratin 15, a putative hair follicle stem cell marker. In the hair mesenchyme, during early stages of hair morphogenesis, Runx1 is expressed in a discrete dermal sub-epithelial layer, while at later stages it is found in a hair cycle dependent pattern in the dermal papilla. To elucidate the function of Runx1 in the hair follicle we have generated a Runx1 epidermal conditional knockout and found that the mutant mice display a remarkable structural deformation of the zigzag hair type. The data delineate Runx1 as a novel specific marker of several hair follicle cell types and sheds light on its role in hair morphogenesis and differentiation.

Runx1 Directly Promotes Proliferation of Hair Follicle Stem Cells and Epithelial Tumor Formation in Mouse Skin

“…In contrast, we detected strong signal in the upper infundibular area, where Runx1 is normally weak in adult mouse skin, and also in both the outer and the inner root sheath, as previously documented for adult mouse skin (44). We conclude that the overall expression pattern of Runx1 documented here in human skin is similar to the expression found in mouse skin during the hair cycle (44,47), suggesting conserved functions in mouse and human HFs.…”

“…To begin to understand if Runx1 might be a potentially interesting therapeutic target in humans, we examined the Runx1 protein expression pattern in human skin. Previously, Runx1 was reported to be expressed at anagen in the outer root sheath of human HFs, including the bulge as well as the hair shaft, and in the inner root sheath (52), similar with the pattern reported in mice in anagen (44,47). The hair matrix keratinocytes in the lower bulb and the precortical hair matrix reportedly showed no, or very low, Runx1 expression.…”

“…Runx1 plays developmental roles in several organs, including blood (54), muscle (65), the nervous system (26,69), and hair follicles (HFs) (44,47), by affecting cell survival, proliferation, and differentiation (14). Runx1 is frequently mutated in acute myeloid leukemia and myelodisplastic syndrome (8,38,54).…”

“…Runx1 is expressed in a few HF compartments, including bulge and germ, but not in other skin epithelial structures, such as sebaceous gland and epidermis (44,47). Constitutive epithelial deletion of Runx1 through development affects hair shaft structure, HFSC activation, and anagen onset (44,47).…”

“…Constitutive epithelial deletion of Runx1 through development affects hair shaft structure, HFSC activation, and anagen onset (44,47). However, it remained unclear if Runx1 directly and permanently affected HFSC proliferation and which factors might be implicated.…”