Researchers have discovered that a single molecular event in our cells could hold the key to how we evolved to become the smartest animals on the planet.
Benjamin Blencowe, a professor in the University of Toronto’s Donnelly Centre and Banbury Chair in Medical Research, and his team uncovered how a small change in a protein called PTBP1 spurs creation of neurons – cells that make the brain – that could have fuelled the evolution of mammalian brains to become the largest and most complex among vertebrates.
Brain size and complexity vary 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 they use a remarkably similar repertoire of genes to build organs in the body.
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 due to a process known as alternative splicing (AS), whereby gene products are assembled into proteins, which are building blocks of life.
During AS, gene fragments called exons are shuffled to make different protein shapes. AS enables cells to make more than one protein from a single gene, so total number of different proteins in a cell surpasses the number of available genes.
Blencowe’s previous work showed that AS prevalence increases with vertebrate complexity. So although 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. AS is most widespread in the brain.
“We wanted to see if AS could drive morphological differences in the brains of different vertebrate species,” said Serge Gueroussov, a graduate student in Blencowe’s lab.
Gueroussov previously helped identify PTBP1 as a protein that takes on another form in mammals, in addition to the one common to all vertebrates.
The second form of mammalian PTBP1 is shorter because a small fragment is omitted during AS and does not make it into the final protein shape.
This newly acquired, mammalian version of PTBP1 may hold clues to how our brains evolved, researchers said.
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.
Gueroussov showed that in mammalian cells, the presence of the second, shorter version of PTBP1 unleashes a cascade of AS events, tipping the scales of protein balance so that a cell becomes a neuron.
When Gueroussov engineered chicken cells to make the shorter, mammalian-like, PTBP1, this triggered AS events that are found in mammals.
“One interesting implication of our work is that 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,” said Blencowe.