Research Highlights : Biology
Looking back into the brain’s future
08 June 2007 (Volume 2 Issue 6)
Molecular biologists determine a key compound that regulates brain development
Figure 1: A present-day skate.enlarge image
RIKEN researchers are beginning to unravel details of the sophisticated regulation system which governs development of the forebrain in all non-marine animals with backbones, including mammals. The system is based around a protein known as YY1, which regulates the segments of DNA that organize the activity of the key gene directing development of the head region, Otx2.
The work is significant in that it demonstrates not only the subtlety of developmental regulation systems, but also the great impact they can have on evolution. The genes responsible for development of the head region in vertebrate animals have been highly conserved over time, suggesting that variation in regulation has been responsible for the vast evolutionary changes that have taken place.
Earlier this year, a research team from RIKEN’s Center for Developmental Biology in Kobe showed that, with the exception of the bony fishes, development of the forebrain in vertebrate animals is initiated when the enhancer known as anterior neuroectoderm (AN) activates the Otx2 gene1. Now, the same team has found that AN is itself is dependent on a promoter, and both are regulated by the protein YY1.
The region of the developing embryo where AN has its impact is very small and difficult to work with in vivo. But the team was able to proceed with its studies when it discovered that the AN enhancer was active in the laboratory cell line, F9.
The researchers found that, to activate Otx2, YY1 must bind to both AN and its promoter. Only YY1 with an acetyl group attached, however, will bind to AN, and this form of YY1 occurs only in the anterior head region, not elsewhere.
The group also found that the binding sites for YY1 are highly conserved in an evolutionary line extending from ancestral skates and coelacanth fishes through to mammals (Fig. 1), suggesting that the regulatory system has been in place a very long time.
While YY1 is necessary for Otx2 to function it is not sufficient. Other compounds are involved in the regulatory process. Not only that, but YY1 itself is associated with and affected in different ways by a wide variety of other proteins.
The picture that emerges is one of a complicated regulatory system subject to highly subtle molecular influences, according to the team. There are still many things they would like to find out about it, such as how AN recognizes acetylated YY1 and what other compounds or co-factors are important.
- Takasaki, N., Kurokawa, D., Nakayama, R., Nakayama, J. & Aizawa, S. Acetylated YY1 regulates Otx2 expression in anterior neuroectoderm at two cis-sites 90kb apart. The EMBO Journal 26, 1649–1659 (2007). | article |