Caltech Biologists Identify Gene Thought to Initiate Neural Development
PASADENA— Biologists have identified a gene that determines whether a given cell in a human or animal embryo will become a neuron rather than some other kind of cell.
In an article appearing in today's journal Cell , California Institute of Technology Professor of Biology David Anderson and his colleagues announce that the gene encodes neurogenin, a member of the basic-helix-loop-helix (bHLH) family of proteins, which in turn control the activity of other genes. When neurogenin RNA appears in cells of the early embryo, the research shows, a genetic chain-reaction begins that turns the cell into a neuron.
According to Anderson, the discovery provides an important piece of information about how embryonic cells develop into cells with specific functions and locales within an organism. Up to a certain stage, all cells in an early embryo look alike in a microscope. But forces are at work that determine whether a specific cell will be a neuron, a muscle cell, a germ cell for sexual reproduction, or any of the other types of cell that make up an organism.
"It's been clear for decades that cells are different in an invisible way long before we are able to see them as being visibly different," says Anderson. "The idea has been that there must be specific genes that confer this invisible predisposition on particular cells."
To demonstrate that neurogenin indeed fulfills such a function, Anderson's coauthor Chris Kintner of the Salk Institute injected tiny amounts of neurogenin RNA in the embryo of a toad. Kintner performed the procedure on the left side of toad embryos at the two-cell stage, so that the effect of the injection could be traced as early in development as possible. The right side was left untouched so that it could serve as a "control."
As each embryo continued to grow by means of cell division, the side that had been flooded with neurogenin RNA became filled with neurons, while the right side developed in a normal manner. This indicated to the researchers that neurogenin is the substance that begins the cascade of genetic steps that turn an undifferentiated cell into a neuron.
Importantly, Anderson, Kintner and colleague Qiufu Ma (a research fellow in biology at Caltech) showed that, once cells make neurogenin, they inhibit their neighbors from becoming neurons by inhibiting their production of neurogenin. Thus, uncommitted embryonic cells are engaged in a winner-take-all competition to become neurons, the winner being decided by the cell that makes the highest level of neurogenin.
The research also showed that other genes suspected of being the initiators of neural development, such as neuroD, actually come into play later after the process has been started by neurogenin. Moreover, the fact that mouse neurogenin RNA can also be successfully used to artificially activate neurogenesis in frog embryos suggests that little difference exists in the gene from species to species.
"The neurogenin (used in the research) is probably about 80 percent identical in its 'business end' to that in humans," Anderson said.
The research builds on earlier work done by J. E. Lee and the late Harold Weintraub at the Fred Hutchinson Cancer Research Center in Seattle, Washington, as well as work done by others on the early development of nerve cells in fruit flies.