A master repressor protein, Tcf3, holds stem cells back until the time is right
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For stem cells, timing is key: To maintain their versatility they rely on a molecular mechanism that keeps the cells in a state of self-renewal until they are needed by adjacent tissue. Now, new research by Rockefeller University’s Elaine Fuchs reveals that in skin, the Tcf3 protein is a critical component of this mechanism, where it functions both to keep stem cells from differentiating and to motivate them to a specific lineage when the time is right.
In adult skin, a reservoir of stem cells is thought to reside in a region of each hair follicle known as the bulge, where the cells are used to provide new hair growth and to repair epidermal wounds. Stem cells in the follicle bulge remain at rest until needed in a new hair follicle cycle or for wound repair. But the bulge is surrounded by differentiated cells, and so how the stem cells maintain their undifferentiated state has remained a mystery. In research published this year in Cell, researchers have fingered Tcf3 as a master regulator of differentiation, showing that it is expressed first in the uncommitted cells of embryonic skin and then, as fates are specified, it becomes restricted to the region of the hair follicle that will become the bulge of the mature hair follicles.
“We have known for a long time that Tcf3 is expressed in the bulge, where the multipotent stem cells of the skin reside,” says Fuchs. “But we didn’t anticipate that Tcf3 would also be expressed in embryonic progenitors and act as a global repressor of all three of the differentiated states — epidermis, hair follicle and sebaceous gland — afforded to these cells.”
Tcf3 is part of the Tcf/Lef family of DNA binding proteins that are best known as partners for the protein beta-catenin. In skin stem cells, molecular signals continually repress beta-catenin, until the cell receives a Wnt protein signal. When this happens, beta-catenin becomes stabilized, allowing it to associate with Tcf/Lef proteins and turn on genes in the stem cell that activate it to divide and start down a path of differentiation. Fuchs and her colleagues wondered whether Tcf3 may have a function in stem cells even during times when the cells were not exposed to Wnt signaling.
“I wanted a system where I could control the expression of Tcf3 in order to monitor its effects in the absence of Wnt signaling,” says Hoang Nguyen, a postdoc in Fuchs’s lab and first author of the paper. “I created a mouse in which I could re-activate Tcf3 at any time. When Tcf3 is turned on in proliferating skin cells postnatally, differentiation of the epidermis, sebaceous gland and hair follicles is blocked.”
Using microarray analysis, Nguyen next compared the gene profiles of the bulge stem cells, embryonic skin and the cells that had re-activated Tcf3. “A group of genes that were affected when I turned Tcf3 back on in mice were also characteristic of the natural pattern of gene expression seen in bulge cells and in undifferentiated embryonic skin,” says Nguyen.
“Our prior studies revealed a role for Wnt signaling in stem cell activation and maintenance. Hoang’s findings have now uncovered a role for Tcf3 in stem cells even when Wnt signaling is absent,” says Fuchs. “It is becoming increasingly clear that Tcf/Lef proteins and Wnt signaling play very important roles in stem cell biology, and our studies on skin stem cells should provide insights relevant to other stem cells of the body, including embryonic stem cells.”
