Proteins in fluids bathing the brain are essential for building the brain, discover scientists in a report published March 10 in the journal Neuron. The finding promises to advance research related to neurological disease, cancer and stem cells.
Before now, the fluid surrounding the brain was generally considered to be a sort of salt-solution that simply maintained the brain's ionic balance. Recent reports of fluctuating proteins in the fluid suggested otherwise, however. And thus, a multi-institutional research teams at the Children's Hospital in Boston, led by Maria Lehtinen, Mauro Zappaterra and Christopher Walsh and researchers from the George Washington University School of Medicine and Health Sciences in Washington, D.C., decided to take a closer look at what proteins in the fluid do. What they found shocked them: As embryos and their brains are growing, a type of protein that tells brain cells to multiply increases in the so-called cerebrospinal fluid.
"This study is a game changer," says Anthony LaMantia, director of the GW Institute for Neuroscience at the GW School of Medicine and Health Sciences and an author on the paper, along with Thomas Maynard, Associate Professor of Pharmacology and Physiology at GW. "It's remarkable that signals are coming from the cerebrospinal fluid - it makes sense but no one really thought about it in this way."
Brain cells in the cortex -- the part of the brain responsible for cognition, learning and memory -- multiply and move to their appropriate position between the second and third trimester of embryonic development in humans. But until now, researchers have had little luck finding the molecular signals that direct the process as well as determining how the signals get delivered to the cells that need them.
The current team extracted cerebrospinal fluid from mouse embryos around two weeks after conception, when their brains develop most quickly. The fluid contained high levels of a protein, insulin-like growth factor or Igf2, which is known to help stem cells multiply and differentiate. Notably, the protein isn't elevated after birth. When the authors blocked Igf2, stem cells in the brain stopped making brain cells, which resulted in abnormally tiny mice brains. And when the team placed brain stem cells in a dish filled with Igf2-rich, embryonic cerebrospinal fluid, the cells proliferated rapidly. "This was clearly the environment the stem cells needed to be happy," LaMantia explains.
Brain cell proliferation is only a good thing when the time is right, however. After all, unrestrained cell multiplication leads to tumors. According to this report, Igf2 knows it's time to activate in the fluid because of proteins in long cells that surround the fluid. These long glial cells stretch from the inner part of the brain, where the fluid is, to its outer layer. They form early in brain development, and younger brain cells crawl along them during development as they find their appropriate positions like patrons filing into an opera house. At the innermost-end of the cells, at a spot called the apical domain, two proteins regulate Igf2 by altering other proteins at the surface of the glial cells, which bind to Ifg2.
If one of the steps in this pathway goes awry, Ifg2 could be activated at the wrong time causing uncontrolled proliferation. Indeed, brain cancer patients with the worst prognosis appear to have the highest levels of Igf2.
However, the fact that vital signals are sent from cerebrospinal fluid could be good news for cancer patients. "It's difficult to deliver a drug that will influence a specific spot within the brain tissue," says LaMantia. Instead, clinicians might one day infuse brain fluid with medicine - possibly one that blocks the signals from Igf2 telling cells to proliferate. "The possibilities for using the fluid as an efficient mechanism to deliver small molecule drugs are endless," he says.
Stem cell researchers now have another possible mechanism to explore in regards to how stem cells in other parts of the body differentiate and multiply. Perhaps researchers might find important proteins in what was thought to be benign fluid associated with the lungs, intestines, or other organs.
Finally, the study contributes to research on schizophrenia, autism and other neurological disorders thought to result from an erroneous arrangement of brain cells. Researchers must learn how brain development goes awry before they can design treatments, and therefore they must know how brain cells proliferate and move to the right position normally.
"This study was a massive undertaking requiring multiple labs with different resources," says LaMantia. "This is a remarkable line of investigation, and there are enormous possibilities for future work in this area."
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