Foxd3 gene allows stem cells to remain stem cells

Foxd3 joins the small, but growing list of stem cell regulating genes

In the search to understand the nature of stem cells, researchers at the University of Pennsylvania School of Medicine have identified a regulatory gene that is crucial in maintaining a stem cell’s ability to self-renew. According to their findings, the Foxd3 gene is a required factor for pluripotency – the ability of stem cells to turn into different types of tissue – in the mammalian embryo. Their research is presented in the October 15th issue of the journal Genes and Development.

“Stem cells represent a unique tissue type with great potential for disease therapy, but if we are to use stem cells then we ought to know the basis of their abilities,” said Patricia Labosky, PhD, an Assistant Professor in the Department of Cell and Developmental Biology. “Among the stem cell regulatory genes, it appears that Foxd3 gene expression keeps stem cells from quickly differentiating – that is, developing into different types of tissue – holding back the process so that an embryo will have enough stem cells to continue developing normally.”

To study the function of the Foxd3 gene, Labosky and her colleagues generated mice with an inactivating mutation in the gene, and then analyzed those mice to determine the role of the Foxd3 protein.

Foxd3-deficient embryos do not survive very long. While part of the yolk sac forms, the inner cell mass that contains all the cells that make up the body of the developing embryos fails to expand enough to produce the embryo and some of the supportive tissues. Without Foxd3, the mouse embryos simply could not maintain enough stem cells to survive a crucial point in their development.

“Our findings implicate Foxd3 as one of the few genes serving as a ’master switch’ of the developing embryo,” said Labosky. “These genes determine the fate of cells by turning on or off other genes in response to signals in the embryo.”

Foxd3 joins previously identified genes, such as Oct4, Fgf4, and Sox2, which control the pluripotency of embryonic stem cells in the early stages of embryogenesis. In their experiments, Labosky and her colleagues found that these genes are still expressed despite the lack of Foxd3. This suggests Foxd3 functions either downstream of Oct4, Fgf4 and Sox2, or along a parallel pathway.

The researchers determined that normal embryonic development can be restored by adding non-mutant embryonic stem cells to the Foxd3-mutant embryos, indicating that Foxd3 acts in the inner cell mass and its derivatives. According to Labosky, Foxd3 is a key regulator of mammalian stem cells, with a clear counterpart in humans. Foxd3 gene expression is a diagnostic characteristic of human embryonic stem cells, suggesting that the gene may function in a similar fashion in mouse and human cells.

“If we are to take advantage of stem cells as a clinical therapeutic, then it is absolutely vital to identify the key regulatory genes such as Foxd3 that control the process of cell differentiation,” said Labosky. “Once we understand how these genes function we are that much closer to being able to mold stem cells to meet our needs.”