Co-factors of LIM domains (Clims/Ldb/Nli) regulate corneal homeostasis and maintenance of hair follicle stem cells

Abstract

The homeostasis of both cornea and hair follicles depends on a constant supply of progeny cells produced by populations of keratin (K) 14-expressing stem cells localized in specific niches. To investigate the potential role of Co-factors of LIM domains (Clims) in epithelial tissues, we generated transgenic mice expressing a dominant-negative Clim molecule (DN-Clim) under the control of the K14 promoter. As expected, the K14 promoter directed high level expression of the transgene to the basal cells of cornea and epidermis, as well as the outer root sheath of hair follicles. In corneal epithelium, the transgene expression causes decreased expression of adhesion molecule BP180 and defective hemidesmosomes, leading to detachment of corneal epithelium from the underlying stroma, which in turn causes blisters, wounds and an inflammatory response. After a period of epithelial thinning, the corneal epithelium undergoes differentiation to an epidermis-like structure. The K14-DN-Clim mice also develop progressive hair loss due to dysfunctional hair follicles that fail to generate hair shafts. The number of hair follicle stem cells is decreased by at least 60% in K14-DN-Clim mice, indicating that Clims are required for hair follicle stem cell maintenance. In addition, Clim2 interacts with Lhx2 in vivo, suggesting that Clim2 is an essential co-factor for the LIM homeodomain factor Lhx2, which was previously shown to play a role in hair follicle stem cell maintenance. Together, these data indicate that Clim proteins play important roles in the homeostasis of corneal epithelium and hair follicles.

Cofactors of LIM Domains Associate with Estrogen Receptor α to Regulate the Expression of Noncoding RNA H19 and Corneal Epithelial Progenitor Cell Function

“…Known to be important for stemness, CLIM2 is required for the maintenance of fetal and adult hematopoietic stem cells (5). It is also required for maintenance of epithelial stem cells in the crypts of the small intestine (6), in the bulge of hair follicles (7), and in the basal layer of the mammary gland (8). Intriguingly, CLIM2 has also been shown to regulate the final stages of erythroid differentiation (9).…”

“…To avoid the embryonic lethality and the complex issue of redundancy, we developed a mouse expressing a dominant negative (DN) CLIM under the Krt14 promoter (K14-DN-Clim), targeting DN-CLIM to the basal layer of stratified epithelial tissues, including epidermis, hair follicles, mammary gland, and cornea (7,15). The K14-DNClim mice exhibit decreased numbers of hair follicle stem cells, resulting in hair loss, and have abnormal corneas (7).…”

“…Right after birth, the K14-DN-Clim mice develop epithelial hyperplasia and corneal opacity (7). Due to defective cell adhesion, caused at least in part by decreased expression of the hemidesmosome component BP180, stromal edema and blistering frequently occur, resulting in a strong inflammatory reaction and neovascularization.…”

Modularity of CHIP/LDB transcription complexes regulates cell differentiation

“…In mice the LDB1-LHX2 complex functions in the maintenance of stem cells in hair follicles 10,47 and possibly in limb development. 48 a similar function was suggested for LDB1 in intestinal crypts 49 and for LDB1, 50 and LHX2, 51 in hematopoiesis.…”

Ephrins Negatively Regulate Cell Proliferation in the Epidermis and Hair Follicle

“…To assess which Eph receptors and ephrins that are expressed in the skin, we first analyzed publically available microarray data derived from either telogen [29] or early and late anagen hair follicles [30] from adult mouse whole back skin. We found that several members of both A and B class receptors and ligands were expressed in telogen follicles (Fig.…”