Howard Hughes Medical Institute researchers have discovered a novel way in which the brain size of developing mammals may be regulated. They have identified a signaling pathway that controls the orientation in which dividing neural progenitor cells are cleaved during development.
The way these cells are sliced during development is critical because at later stages of neurogenesis, vertical cleavage gives rise to two mature neurons that are incapable of further division, while horizontal cleavage yields one neuron and one progenitor cell that can continue to support brain growth.
The researchers speculate that this type of regulatory decision point may play a powerful role in determining the ultimate size of the mammalian brain. Inherited disorders that cause the brain to develop too small or too large may also influence this developmental pathway.
Howard Hughes Medical Institute investigator Li-Huei Tsai and postdoctoral fellow Kamon Sanada, both at Harvard Medical School, published their findings in the July 15, 2005, issue of the journal Cell.
The researchers drew on studies by other researchers that showed that the orientation of cleavage planes in dividing neural progenitor cells in the neocortex determines the fate of the resulting daughter cells. However, nothing was known about the molecular signaling mechanism that regulates the decision to cleave one way or another, said Tsai.
Studies in fruit flies and roundworms had hinted that major regulatory molecules called heterotrimeric G proteins play a role in orienting the mitotic spindles that govern the orientation of cell cleavage during cell division, or mitosis.
"Based on that knowledge, we knew that heterotrimeric G proteins were very good candidates as regulators of the plane of cell division in neural precursors," said Tsai.
"And this is a very important question, because how these cells divide ultimately determines the final number of cells that will be generated during brain development," she said.
Using the embryonic mouse brain as a model, Sanada and Tsai sought to determine whether G proteins play a role in the developing mammalian brain. In their initial experiments, they impaired the function of the Gâã subunits of heterotrimeric G proteins, in the developing mouse brain. They saw a dramatic interference with orientation of cell cleavage to overproduce "postmitotic" neurons -- cells that could no longer divide -- at the expense of progenitor cells, which could still divide. "This observation led us to want to further test whether impairment of Gâã has any consequences for cell fate in division, because it has been speculated that the different division planes dictate the ultimate cell fate adoption of daughter cells," said Tsai.