A protein that has the same exact amino acid sequence in mice and humans, plays an entirely novel role in human brain development, new research reports. X. Zhang et al. "Pax6 is a human neuroectoderm cell fate determinant,"Cell Stem Cell,7: 90-100. 2010.
Su-Chun Zhang and colleagues at University of Wisconsin-Madison analyzed Pax6 expression and function in human embryonic stem cells (hESCs), human fetuses, and human induced pluripotent stem (iPS) cells. This is one of the few papers that analyzes gene expression in human embryos, and although controversial, justifies how important this is.
Pax6 is one in a family of paired box (Pax6) transcription factors that control embryonic development in a variety of cell lineages. The best-studied of the Pax factors, Pax6 is highly conserved and important to the development of eyes, pancreas, and cerebrum across many species. In mice, Pax6 expression is detected in later stages of neural stem cell development, when the cerebrum begins to develop. But with a lack of human models, little was known how Pax6 affects human embryonic development. When Zhang's team silenced Pax6 in mouse ESCs, the cells still generated neural stem cells when other factors, such as Sox proteins, compensated. But when they did the same in human ESCs, no neural stem cells developed, either in a Petri dish or in vivo.
Through a series of additional experiments, the team found that Pax6 is responsible for suppressing stem cell genes, like Oct4 and Nanog, while simultaneously activating neural-specific genes. Because of these dual roles, Zhang said, it is appropriate to call Pax6 a "master switch," turning some genes on and others off. The factor is so powerful, said Zhang, that even when the researchers tried to block the development of neural cells through three different non-genetic methods, such as adding factors to guide ESCs toward a mesoderm fate, Pax6 won out. As long as the factor was being expressed, cells went on to become neurons.
Since Pax6 so strongly drives hESCs to become neural stem cells, the team is now looking to see if Pax6 can also be used to maintain an adult population of those same cells. While ESCs and iPS can be maintained in a pluripotent state, it is currently very difficult to do the same in adult somatic stem cells -- over time they begin to differentiate and lose their potential. Zhang is also interested in seeing if Pax6 can reprogram other adult cells directly into neural stem cells, skipping the iPS cell state altogether.