Stem Cell Depletion Through Epidermal Deletion of Rac1

Abstract

Mammalian epidermis is maintained by self-renewal of stem cells, but the underlying mechanisms are unknown. Deletion of Rac1, a Rho guanosine triphosphatase, in adult mouse epidermis stimulated stem cells to divide and undergo terminal differentiation, leading to failure to maintain the interfollicular epidermis, hair follicles, and sebaceous glands. Rac1 exerts its effects in the epidermis by negatively regulating c-Myc through p21-activated kinase 2 (PAK2) phosphorylation. We conclude that a pleiotropic regulator of cell adhesion and the cytoskeleton plays a critical role in controlling exit from the stem cell niche and propose that Rac and Myc represent a global stem cell regulatory axis.

Requirement of Rac1 distinguishes follicular from interfollicular epithelial stem cells

“…The aberrant hair follicle formation upon Rac1 gene deletion during development is aligned with the observation that Rac1 excision in adult animals leads to the rapid disappearance of follicular stem cells and the consequent hair loss (Benitah et al, 2005). However, whereas we did not observe any major alterations in the epidermis caused by Rac1 deficiency, the use of tamoxifen-activated Cre to excise the Rac1 gene in adult mice provoked a burst of cell proliferation followed by rapid differentiation and loss of growth capacity, resulting in skin thinning and ulceration (Benitah et al, 2005).…”

“…The epidermis is not dependent on Rac1 expression Surprisingly, however, Rac1 gene excision in the epidermis did not have any major effects in the interfollicular compartment (Figure 3a), in contrast to Rac1 is dispensable for epidermis formation RM Castilho et al the results obtained by the activation of Cre upon topical application of tamoxifen (Benitah et al, 2005). Histological analysis of the interfollicular skin showed no remarkable morphological alterations (Figure 3a) associated with the absence of Rac1 protein (Figure 3b).…”

“…Control mice showed well organized hair follicles distributed in parallel rows and follicles grouped in sets of three (Figure 2b), but K14Cre Rac1 F/F mutant mice showed no row organization, lack of follicle sets and a reduction in hair follicle size (Figure 2b). Of direct relevance, during the course of these experiments, Benitah et al (2005) reported that conditional deletion of Rac1 in adult mice results in the loss of epithelial stem cells. Indeed, aligned with this possibility we observed that K14Cre Rac1 F/F mice did not display the presence of LRC in the skin at weaning (P21) (Figure 2c), whereas BrDU positive cells were observed in the hair follicle bulge area of control mice.…”

The circadian molecular clock creates epidermal stem cell heterogeneity

“…The nature of such niche heterogeneity is currently unknown. Importantly, perturbing the equilibrium between the responsive and non-responsive stem cell states causes tissue malfunction and increases the risk of carcinogenesis [16][17][18][19][20] .Here, we analysed the role of the molecular clock in fine-tuning the function of epidermal stem cells. The mammalian clock machinery anticipates and synchronizes vital functions related to the physiological circadian needs of the organism 21 .…”

“…The nature of such niche heterogeneity is currently unknown. Importantly, perturbing the equilibrium between the responsive and non-responsive stem cell states causes tissue malfunction and increases the risk of carcinogenesis [16][17][18][19][20] .…”