The Role of the Rac1 Protein in the Hair Follicle Stem Cell Niche
The hair follicle stem cell niche is a term referring to the microenvironment of stem cells that are vital to the maintenance of the epidermis and the regeneration of hair and sebaceous glands. By controlling the signalling and activation of various proteins and molecules in the niche, proliferation and migration of stem cells can be tightly controlled. Through the Wnt Signalling Pathway, it has been found that the Rac1 protein; a GTPase of the Rho family of G-proteins, is involved in controlling stem cell differentiation and proliferation in the hair follicle stem cell niche, as well as growth and cell-cell adhesion (Benitah et al. 2005). Upon activation by the GTP exchange factor, Tiam1, Rac1 inhibits the expression of the c-Myc transcription factor through the phosphorylation of PAK2. Thus Rac1 prohibits differentiation of stem cells by securing the interaction of stem cells with the niche. An experiment conducted to determine the function of the Rac1 protein, examined the effect of the absence of the protein by deleting the gene coding for it in mice. It was found that hair growth as well as epidermal maintenance was severely compromised as a result.
The Hair Follicle Stem Cell Niche
A niche in the context of stem cells refers to each individual cell's microenvironment (Li and Xie, 2005). The hair follicle stem cell niche is located in the outer root sheath area of the hair follicle, also known as the bulge (Li and Xie, 2005). Hair follicle stem cells are integral to the maintenance of the epidermis and the regeneration of hair and sebaceous glands of the hair follicle (Moore and Lemiscka, 2006). The niche of a stem cell, comprised of the signals released by the cells of the niche, monitors both cell proliferation as well as migration. The cellular microenvironment of stem cells also protects them from external stimuli that may trigger events
such as differentiation and apoptosis, which in turn compromise stem cell identity (Moore and Lemiscka, 2006). The identity of stem cells within the bulge is maintained predominantly by the Rac1 protein; a GTPase of the Rho family of G-proteins. Rac1 is responsible for not only extrinsically regulating the exit of stem cells from the niche (Chrostek et al., 2006), but also signalling, cell-cell adhesion, and cellular growth (Benitah et al., 2005).
Upon division of stem cells, two types of daughter cells are produced. One type of daughter cell remains in a multipotent state to maintain stem cell numbers, while the second type of daughter cell is able to undergo rapid proliferation followed by differentiation and are called transient amplifying cells (Ohyama et al., 2006). By migrating upward in the hair follicle, transient amplifying cells can differentiate into epidermal progenitor cells, thereby maintaining the epidermis, while downward migrating transient amplifying cells act as hair matrix progenitors as they migrate from the bulge to the bulb, thus initiating another cycle of hair follicle growth (Castilho et al., 2005).
Functions of Rac1
Rac1 is a GTPase of the Rho family of G-proteins and is involved in the maintenance of stem cells in the hair follicle stem cell niche (Chrostek et al., 2006). To further examine the functions of the Rac1 protein in the niche of hair follicle stem cells, an experiment was conducted by a group of researchers at the Max Planck Institute of Biochemistry. Mice with a deletion of the gene coding for this protein were developed. This was accomplished using 40HT (4-hydroxy tamoxifen) on the skin of the mice (Benitah et al., 2005). Following the experiment, it was found that these mice not only lost all of their hair within 2 months of birth, but also showed an overall reduction in the number of epithelial stem cells. Also, little to no hair growth was observed later
in life. The researchers thus concluded that not enough epithelial stem cells were kept in a multipotent state. Based on these results it was confirmed that the Rac1 protein is essential for controlling the exit of epithelial stem cells from the hair follicle niche (Chrostek et al., 2006). A deletion of the gene coding for the Rac1 protein in mice therefore results in the stimulation of stem cell differentiation and rapid depletion of stem cells in the hair follicle stem cell niche (Benitah et al., 2005).
The Rac1 protein can exist in an active GTP-bound form and an inactive GDP-bound form (Chrostek et al., 2006). The protein cycles between the inactive and active form upon phosphorylation of GDP to GTP. This phosphorylation of GDP, converting Rac1 into its active form is catalyzed by a GTP exchange factor called Tiam1, as can be seen in Figure 2 (Dotto and Cotsarelis, 2005). Upon activation of Rac1, the protein is able to control differentiation of stem cells in the niche. In the hair follicle stem cell niche, Rac1 phosphorylates PAK2 (p21-activated kinase2), allowing it to negatively regulate the expression of the c-Myc transcription factor. In the presence of activated Rac1, c-Myc is inhibited and therefore loses it functions within the cell. The c-Myc transcription factor, when activated by Lef/Tcf through the Wnt Signalling Pathway in the absence of Rac1, induces differentiation of hair follicle stem cells by disturbing the interactions between the cells comprising the niche and the hair follicle stem cells (Moore and Lemiscka, 2006) (Benitah et al., 2005). As it can be seen in Figure 1, Rac1 exerts its effects through the inhibition of c-Myc through the Wnt Signalling Pathway, resulting in the controlled differentiation of hair follicle stem cells. In the absence of Rac1, stem cell proliferation is not controlled, and the transcription factor c-Myc allows rapid proliferation which depletes the stem cell numbers in the niche. While Rac1 is active, c-Myc is inhibited, thus stem cell proliferation is controlled and stem cell quantity is sustained (Dotto and Cotsarelis, 2005).
As in all systems of an organism, cell differentiation and proliferation must be tightly regulated and thus with regard to stem cells, very specific mechanisms are in place to maintain a balance of differentiated and undifferentiated cells. In the hair follicle stem cell niche, Rac1, among several other regulatory proteins are involved in controlling the exit of stem cells from the niche, cellcell adhesion and signalling (Benitah et al., 2005). Stem cells from the hair follicle stem cell niche can go on to form two types of daughter cells, ones that remain as stem cells, and others that can undergo differentiation and can become epidermal cells, or hair matrix progenitor cells depending on their migration in the hair follicle (Castilho et al., 2007). Studies conducted to examine the exact function of the Rac1 protein have attempted to do so by looking at the effect of the absence of the protein. One such experiment discussed in this paper found a significant impact on hair growth and epidermal maintenance. The more pronounced effect however was on hair growth, indicating that the role of Rac1 is targeted more toward hair growth (Chrostek et al., 2006). Currently there is much left to discover regarding the functions and targets of the Rac1 protein. A more thorough understanding of the mechanisms by which this protein functions can give tremendous insight into the treatment of severe wounds, the aging process of the skin and prevention as well as treatment for hair loss (Ohyama et al., 2006).
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