University of Toronto researchers have discovered a brain protein that could shed light on the underlying causes of brain disease such as Alzheimer’s.
Researchers characterized a previously unknown regulatory protein known as nSR100 and described its role in neuronal development. This marks the first time this family of proteins has been found to play a specific role in tissue development in the body. The findings were published in the prestigious journal Cell last month.
The nSR100 protein functions by regulating “alternative splicing events” in target genes. It acts to increase the complexity and diversity of the nervous system’s cells by tailoring neurons to perform the specific functions that distinguish them from other cell types. The process of alternative splicing is akin to editing a film: nSR100 works with the raw footage of the genetic code to cut the unnecessary scenes and determine which of the required segments are pasted together.
This specific type of protein is found only in vertebrate genomes, which suggests it evolved to enhance cell diversity in the nervous systems. The team’s findings may partially explain why less complex organisms, such as nematode worms, have simpler nervous systems. Humans can produce a much larger array of cellular messages from roughly the same number of genes as nematodes through the action of tissue-specific splicing regulators, such as nSR100. These messages can then act in concert to orchestrate the diversification of functions in specific tissue systems.
A graduate student in the Department of Molecular Genetics, John Calarco, began the search for a nervous system alternative splicing regulator over four years ago under the supervision of professor Ben Blencowe (Donnelly Centre for Cellular and Biomolecular Research) and professor Mei Zhen (Samuel Lunenfeld Research Institute, Mount Sinai Hospital). After a computational search of mammalian genomes they idenfified nSR100, a member of the SR protein family, as a potential candidate. Its expression was then tested experimentally and found to be present specifically in the nervous tissue of mice and zebrafish. Calarco and colleagues then performed a series of additional biochemical experiments to confirm that nSR100 contributes to fine-tuning the expression of
genes to customize undifferentiated cells into brain-specific cells through alternative splicing.
The authors noticed that their computational search identified more than 100 RS domain protein genes, many of which are yet to be studied. In other words, scientists are sitting on a potential treasure trove of proteins that may unravel some of the darkest mysteries lurking in the human genome.
Such discoveries are leading the way to a new paradigm shift in molecular genetics. Rather than survey the expression of thousands of mRNAs (the chemical messengers that turn the info in DNA into proteins), scientists can now observe more complicated aspects of RNA processing, including alternative splicing, to get at the heart of how gene expression is regulated. Now the race is on not only to identify proteins that regulate cell development, but also to describe how all those proteins act together to develop the complexity of the human body, and particularly the brain.
According to Calarco, “The brain is a playground for many factors that coordinately control numerous ‘layers’ of gene regulation. A major goal now is to figure out how these various layers communicate with each other to generate the incredible degree of cellular and molecular diversity observed in the vertebrate nervous system. Further investigation into the network of splicing events regulated by nSR100 may uncover important aspects of how neurons normally function and also how they become impaired in neurological diseases like Alzheimer’s.
The opportunity to study the brain’s complexity drew Calarco to pursue research in neurogenetics as a graduate student at U of T. He began his research career as a modest research assistant mixing solutions in professor Blencowe’s lab. Calarco advises undergraduates interested in pursuing research to ask lots of questions and get lab experience early. Learning the ropes in a laboratory environment will help determine whether research is a good fit and give young researchers the skills and contacts to become innovators in emerging fields.
Calarco plans to continue exploring neuronal gene expression with a post-doctoral fellowship in neurobiology and to eventually run his own independent ‘gene searching’ lab. His work demonstrates that great research is about asking the right types of questions, and when it comes to brain research, it’s a lot to wrap your head around.
Funding for this project was provided by the Canadian Institute of Health Research, the Ontario Research Fund, and Genome Canada (through the Ontario Genome Project).
