Schematic representation of PTBP1 protein structure. Each RNA recognition motif (RRM) has different binding affinity for pyrimidine-rich sequences on mRNA. The N-terminal domain encloses partially overlapping nuclear localisation (NLS) and export signals (NES). Blue boxes representing RRMs are not drawn to scale.
A small change in a protein PTBP1 can spur the creation of neurons that could have fuelled the evolution of mammalian brains to become the largest and most complex among vertebrates. Brain size and complexity vary enormously across vertebrates, but it is not clear how these differences came about. Humans and frogs, for example, have been evolving separately for 350 million years and have very different brain abilities. Yet scientists have shown that they use a remarkably similar repertoire of genes to build organs in the body.
So how is it that a similar number of genes, that are also switched on or off in similar ways in diverse vertebrate species, generate a vast range of organ size and complexity?
This image shows a frog and human brain, brought to scale. Although the brain-building genes are similar in both, alternative splicing ensures greater protein diversity in human cells, which fuels organ complexity. Credit: Jovana Drinjakovic
The key lays in the process that Blencowe’s group studies, ie alternative splicing (AS), where gene products are assembled into proteins. During AS, gene fragments, exons, are shuffled to make different protein shapes. It’s like LEGO, where some fragments can be missing from the final protein shape. AS enables cells to make more than one protein from a single gene, so that the total number of different proteins in a cell greatly surpasses the number of available genes. A cell’s ability to regulate protein diversity at any given time reflects its ability to take on different roles in the body. Blencowe’s previous work showed that AS prevalence increases with vertebrate complexity. So although the genes that make bodies of vertebrates might be similar, the proteins they give rise to are far more diverse in animals such as mammals, than in birds and frogs.
“We wanted to see if AS could drive morphological differences in the brains of different vertebrate species,” says Serge Gueroussov who previously helped identify PTBP1 as a protein that takes on another form in mammals that is shorter since a small fragment is omitted during AS, in addition to the one common to all vertebrates. Could this newly acquired, mammalian version of PTBP1 give clues to how our brains evolved?
PTBP1 is both a target and major regulator of AS. PTBP1’s job in a cell is to stop it from becoming a neuron by holding off AS of hundreds of other gene products. In mammalian cells, the 2nd shorter PTBP1 unleashes a cascade of AS events, tipping the scales of protein balance so that a cell becomes a neuron. “…this particular switch between the two versions of PTBP1 could have affected the timing of when neurons are made in the embryo in a way that creates differences in morphological complexity and brain size,” says Prof Blencowe in the Department of Molecular Genetics.
http://medicine.utoronto.ca/news/why-we-re-smarter-chickens
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