The size of the brain is regulated by a surprisingly simple mechanism – as far as fish are concerned. Professor Pertti Panula’s team identified the “intelligence gene” pathway in their experiments on zebrafish. But how crucial is this gene for human brain?

Fish with larger brains and higher intelligence have higher expression of a certain gene, Angiopoietin-1.  According to a new study by researchers at the University of Helsinki, University College London (UCL) and Stockholm University when expression levels of Ang-1 are experimentally reduced, brains shrink.

In the study, these trends were seen in two unrelated species of fish – guppies and zebrafish – indicating expression of Ang-1 is important for brain growth and development in fish generally.

The study, published today in Proceedings of the Royal Society B, identified the underlying genetics of natural variation in brain size and cognitive abilities in fish.

Zebra-fish study identified cellular mechanism

Populations of guppies selected for either large or small brains, with associated differences in intelligence, were used for the first step in the study which was a complete genome analysis of differently expressed genes. There was a 10 % difference in brain size between the large and small-brain guppies and from the genetic analysis, Ang-1 was identified as the only gene expressed at different levels in each replicate population.

Further experiments in zebrafish by collaborator professor Pertti Panula at the University of Helsinki confirmed that Ang-1 is a driver for brain size.

In the zebrafish experiments, Angiopoietin-1 also regulated expression of the gene notch 1, known to be essential in differentiation of neural stem cells, Panula says.

"Consistent differences in notch 1 expression were also found in guppies with small and large brains."

Young fish next to be investigated

"We were surprised to see that only a single gene was up-regulated in the large-brained guppies," UCL professor Judith Mank says.

"Given the complexity of the brain, we expected that the genetics would be very intricate, but this suggests that changes in brain size are underpinned by relatively simple genetic mechanisms."

Future studies will aim to investigate the role of Ang-1 and possibly other genes in the formation of differently sized brains in developing embryos.

"Other genes may be involved in brain growth in young, developing fish but no other genes were found to vary in their expression in adult fish other than Ang-1," says Dr Niclas Kolm from the Stockholm University.

The researchers now plan to study the age-specific genetic architecture of both brain structure and function based on new artificial selection experiments in the guppy.

What about humans and other vertebrates?

Ang-1 could play an important role in the brain development of other vertebrates as well, but future research is required to establish this, say the scientists behind the study.

The protein encoded by Ang-1 is known to be significant in growing new blood vessels and forming new brain cells in mice, which may indicate an important role of Ang-1 in brain growth even in humans.

"We don’t yet know if Ang-1 is important in human brain development," professor Judith Mank says.  

It isn’t on the list of genes typically studied in relation to human brain size.

"But as it plays a role in forming new blood vessels in humans, there may be a connection as large brains need a bigger blood supply, particularly during growth and for many brain functions."

"This presents us with an exciting opportunity to investigate the role of Ang-1 across different vertebrates."