Knocking the Sox off early mammalian development

Scientists find key embryonic stem cell gene

Scientists have identified a gene that is required during early mammalian embryogenesis to maintain cellular pluripotency – the ability of an embryonic cell to develop into virtually any cell type of the adult animal. This discovery by Dr. Robin Lovell-Badge and colleagues at the MRC National Institute for Medical Research (London, UK) that the Sox2 gene is necessary to sustain the developmental plasticity of embryonic cells sheds new light on the molecular cues that direct early embryogenesis, as well as the genetic requirements for embryonic stem cell maintenance. The report is published in the January 1 issue of Genes & Development.

“Stem cells must have specific genes that give them their characteristic properties. Our work describes one such gene, Sox2, that appears essential for multipotent stem cell types in the early embryo,” explains Dr. Lovell-Badge.

Early in mammalian development, a pre-implantation stage embryo called a blastocyst forms. The cells of the blastocyst are at a developmental fork in the road: The cells on the surface of the blastocyst become trophoblast cells, while the cells on the inside of the blastocyst become the inner cell mass (ICM). The ICM is further specified into epiblast and hypoblast cells, which, together with trophoblast cells, give rise to the entire embryo and its associated tissues: epiblast cells differentiate into all the cell types of the embryo, hypoblast cells differentiate into the yolk sac, and trophoblast cells differentiate into the chorion and much of the placenta, including a range of specialized cell types.

Dr. Lovell-Badge and colleagues have identified Sox2 as one of the only two known transcription factors (master gene regulators) to be involved in the specification of these three embryonic cell lineages.

“We have been working with this gene for a while, using it, for example, to study stem cells of the nervous system, and simply set out to ask what its critical role is during embryonic development. It turned out to be important very early on – well before the nervous system forms – in two separate cell types: those that give rise to all cells types of the embryo and those that give rise to much of the placenta,” states Dr. Lovell-Badge.

To investigate the developmental role of Sox2, the researchers generated transgenic mice deficient in the gene, or what scientists call “Sox2 knockout mice.” Sox2 knockout mice die as embyos shortly after implantation in the uterus. Dr. Lovell-Badge and colleagues noted that while maternally derived SOX2 protein is present in newly formed embryos, by embryonic day 6.5 the maternal levels of SOX2 dissipate and fatal defects arise in Sox2-deficient embryos.

The researchers found that in Sox2-deficient embryos, the epiblast lineage fails, and only a portion of trophoblast- and hypoblast-derived cells survive. Further work in cell culture confirmed this result in vitro, and also demonstrated that embryonic stem cells cannot be derived from Sox2-deficient embryos. Thus, Sox2 is required to maintain cellular pluripotency both in the developing embryo and in embryonic stem cells.

With this discovery, Sox2 now joins Oct4 as the only identified transcription factors crucial to maintaining embryonic pluripotency. Dr. Lovell-Badge and colleagues show that Sox2 is actually expressed in a broader range than Oct4 in the embryo: While the expression of both genes is required in the ICM and epiblast, only Sox2 is also required to sustain multipotential cells derived from the trophoblast lineage.

Although further research is needed to delineate the precise molecular pathway of Sox2 action, Dr. Lovell-Badge feels confident that Sox2 “helps to define an embryonic stem cell (ES cell) – [and] it will therefore allow us to better understand these cells and perhaps to manipulate them in ways that will be important for stem cell based therapies.”