Critical to the use of embryonic stem cells in therapeutic applications is a thorough understanding of the genetic factors that regulate stem cell fate and preserve the delicate balance between the maintenance of a pluripotent cell population and the differentiation of more specialized cell types. In the October 15th issue of Genes & Development, Dr. Patricia Labosky and colleagues add Foxd3 to the short, but growing list of genes essential for the establishment, maintenance, and differentiation of embryonic stem cells.
Dr. Labosky and colleagues genetically engineered mice to lack Foxd3, and then analyzed the mice to determine the physiological role of the gene and its encoded protein. Foxd3-deficient embryos died early in development (around day 6.5) due to an inability of the inner cell mass to expand normally, and thereby form the embryo proper and some of the supportive extraembryonic tissues (ie., allantois and amnion). The researchers also found that embryonic stem cells, which are derived from the inner cell mass, could not be generated from Foxd3-deficient mouse embryos.
Further analysis by Dr. Labosky and colleagues revealed that the previously identified critical regulators of embryonic pluripotency (Oct4 and Fgf4) appear to be properly expressed in Foxd3-mutant embryos. This finding suggests that Foxd3 functions either downstream of Oct4 and Fgf4, or in a parallel pathway to regulate pluripotency in the early stages of mammalian embryogenesis. Interestingly, normal embryonic development can be restored through the addition of wild-type (genetically normal) embryonic stem cells to the Foxd3-mutant embryos, suggesting that Foxd3 acts through an intercellular signaling pathway in the inner cell mass and its derivatives.
"We believe that Foxd3 is playing a role in maintaining stem cells in an undifferentiated state by regulating the expression of other genes. If we consider the possibilities of using stem cells for therapeutic approaches, it is crucial to understand the factors that provide a stem cell with the defining properties of being able to both self-renew and give rise to multiple cell lineages in the body. Our results suggest that Foxd3 is a critical gene for maintaining these properties," explains Dr. Labosky.