New master switch in brain?

In an unexpected twist, a new study casts a classical protein in a surprising new role: Pax6, a well-recognized factor in brain and eye development in mice, appears to play a very different and crucial part in the development of the human brain. Mature neurons (red) and glial cells (green) derived from hESCs Image courtesy of Su-Chun Zhang The research, reported this week in linkurl:Cell Stem Cell,;https://www.cell.com/cell-stem-cell/ provides "exciting new insights into the fundamental process

Written byMegan Scudellari

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Mature neurons (red) and glial cells
(green) derived from hESCs
Image courtesy of Su-Chun Zhang

The research, reported this week in linkurl:Cell Stem Cell,;https://www.cell.com/cell-stem-cell/ provides "exciting new insights into the fundamental process of neural induction," said linkurl:Kate Storey,;https://www.lifesci.dundee.ac.uk/groups/kate_storey/ a developmental biologist at the University of Dundee in the UK who was not involved in the research, in an email. 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. Now, linkurl:Su-Chun Zhang;https://www.waisman.wisc.edu/faculty/zhang.html and colleagues at the University of Wisconsin-Madison report that Pax6 is also the master regulator of early specification of the neuroectoderm, the outer layer of an embryo that develops into all neural tissues, in humans but not in mice. 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. Zhang decided to analyze its expression and function in human embryonic stem cells (hESCs), human fetuses, and human induced pluripotent stem (iPS) cells. This is "one of few papers analyzing gene expression in human embryos," said Storey. "[That] is an important, if controversial, step forward, and I think the findings of the paper justify this well."

A cluster of neural cells derived from hESCs
Image courtesy of Su-Chun Zhang

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. "It's very different from what we see in animals," said Zhang. Though the protein has the exact same amino acid sequence in mice and humans, it seems to be playing a novel role in human brain development. "The early expression of Pax6 in humans probably has something to do with our unique brain size and intelligence," said Zhang. "For better or for worse," he added with a laugh. Zhang pursued the protein to determine how it works in human neural development. 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. "It's a very powerful factor in humans," he said. 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. "Because of its powerful effect in multiple aspects, we are looking at many areas," said Zhang. X. Zhang et al. "Pax6 is a human neuroectoderm cell fate determinant," Cell Stem Cell, 7: 90-100. 2010.
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