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Johns Hopkins scientists have discovered a protein that appears toplay an important regulatory role in deciding whether stem cells differentiate into the cells that make up the brain, as well ascountless other tissues. This finding, published in Developmental Cell, could eventually shed light on developmental disorders as well asa variety of conditions that involve the generation of new neuronsinto adulthood, including depression , stroke , and posttraumatic stress disorder . Researchers have long known that a small group of proteins calledNotch plays a pivotal role in helping the immature cells present inembryos to develop into the variety of cells present throughout thebody, including those that make up the brain, blood, kidneys andmuscles. "Notch signaling is involved in almost all aspects of tissuedevelopment," explains study leader Valina Dawson, Ph.D., aprofessor in the departments of Neurology, Neuroscience, andPhysiology and co-director of the Stem Cell and NeuroregenerationPrograms at the Institute for Cell Engineering at the Johns HopkinsUniversity School of Medicine. However, she says, even for researchers who have been studyingNotch for decades, how this small group of proteins manages thedevelopment of such a diverse array of tissues and organs in thebody remains unknown. It's a pivotal mystery to solve, Dawson adds,since problems in Notch signaling seem to be involved in various cancers , Alzheimer's disease , juvenile stroke and many other health problems. In their new study, Dawson and her colleagues shed light on one wayNotch proteins might be regulated, through a protein they recentlydiscovered in the lab. This protein seemed to be involved indevelopment, but at first, the researchers didn't know itsfunction. To determine what purpose this protein serves in cells, Dawson,postdoctoral fellow Zhikai Chi, M.D., Ph.D., and their colleaguesstarted by trying to determine what other proteins it's able tobind to. By adding the mystery protein to cell cultures thatexpressed a variety of other proteins, they determined that theunknown protein altered cellular activity in those expressingNotch. Since Notch is involved intimately in determining the fate of brainprecursor cells, driving neural stem cells to proliferate anddetermining whether they become neurons or supporting cells knownas glia, the researchers next examined how this mystery proteinaffected brain development in mouse embryos. They found that byincreasing expression of the unknown protein, more neuronsdeveloped in certain parts of the developing brain, including theintermediate zone and cortical plate. In contrast, decreasingexpression led to fewer neurons. Taken together, Dawson says, theseexperiments provided even more evidence that their unknown proteinwas somehow influencing Notch. To determine exactly how the mystery protein was affecting Notch,the researchers examined the effect of the protein on neural stemcells in the process of differentiating into mature cell types.Increasing the amount of the unknown protein swayed development asif Notch wasn't working. Since the unknown protein appeared toprevent Notch from acting on cells, the researchers named it Botchfor "blocks Notch." With Botch's role now clear, the researchers turned next to themechanism behind how this protein exerts its influence. A series ofexperiments suggests that Botch interacts with Notch in the Golgibody, a cellular organelle involved in modifying proteins. ForNotch to act in development, an immature version of this proteinneeds to be cleaved in order for the protein to be rearranged.Botch appears to prevent this pivotal modification from takingplace, reducing the amount of mature Notch available to do its job. Because Botch appears to play such an important role in regulatingNotch, Dawson says, it could be involved in a number of diseases inwhich the generation of new neurons is misregulated. She and hercolleagues are already performing some preliminary experiments todetermine whether Botch expression might vary from the norm indiseases such as depression, which has been linked to a decrease inneurogenesis in the brain's hippocampus. Eventually, researchersmight be able to develop drugs that act on Botch to restart stalledneurogenesis, potentially treating depression and other diseases inwhich a lack of neurogenesis is thought to play a role. "There are potentially some very large neurological problems thatcould be addressed through changing Botch activity," Dawson says. Additional References Citations. The e-commerce company in China offers quality products such as Optical Fiber Connectors , Fiber Optic Terminal Box, and more. For more , please visit Optical Fiber Splitter today!
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