How does the brain reach its appropriate size? And why are mouse eyes smaller than those of humans? Researchers at the Montreal Clinical Research Institute (IRCM) identified a surprisingly simple biological mechanism that helps answer these questions and sheds new light on how the human nervous system evolved to reach the appropriate size.
In this study, the team discovered that the orientation in which neural stem cells divide during development acts like a powerful cellular “flip switch,” determining how many cells the brain and retina ultimately produce. By altering the orientation of divisions, the researchers were able to generate brain and retinal tissues up to 30% larger than normal, complete with additional layers of cells.
A Simple Cellular Switch With Big Consequences
During development, neural stem cells multiply by dividing in a specific orientation within the growing tissue. In mice, these divisions usually occur in a horizontal direction, a tightly controlled process that limits growth and helps set final organ size.
The IRCM team, led by Dr. Michel Cayouette, found that removing two proteins, namely GPSM2 and SAPCD2, caused these stem cells to divide vertically instead. This reorientation had dramatic consequences.
In the brain, vertical divisions produced large numbers of stem-like cells that continue to multiply. These cells closely resemble outer radial glia, a cell type that is rare in mice but abundant in humans and thought to play a key role in the expansion of the human cerebral cortex.
In the retina, the same reorientation triggered the emergence of a new population of progenitor cells normally absent in mice. These cells behave much like growth-promoting cells found in the developing brain, helping to explain how the retinal tissue expanded so drastically.
Strikingly, when the researchers compared different species, they found that the human and macaque retina naturally show higher rates of vertical stem-cell divisions than mice, along with more growth-promoting cells, suggesting that this cellular “flip switch” is a conserved mechanism that drives nervous system expansion across species.
“Changing the angle of a stem cell’s division might seem like a small detail,” says Dr. Cayouette, “but it turns out to be a major control point for how many cells the nervous system produces, and ultimately, how big it becomes.”
Linking Cell Division to a Master Growth Pathway
The researchers traced the effects of this division switch to the Hippo signalling pathway, a well-known molecular system that regulates organ size throughout the body.
When stem cells divide vertically, key components of the Hippo pathway are unequally distributed between the two daughter cells. This imbalance pushes one of the cells to keep dividing, fuelling tissue growth.
“This provides a direct molecular link between the geometry of cell division and the global control of organ size,” explains Dr. Benoit Boulan, a postdoctoral fellow in the Cayouette laboratory and first author of the study.
Implications for Human Development and Disease
Beyond its evolutionary implications, the discovery offers a powerful new framework for studying human developmental disorders marked by abnormal brain size or structure, including conditions such as microcephaly and cortical malformations.
By experimentally controlling the orientation of stem-cell divisions, researchers can now explore how subtle molecular disruptions during early development may lead to profound and lasting effects on the brain and eye.
The team wishes to thank Anna La Torre (UC Davis) and Alain Chédotal, as well as The Canadian Institutes of Health Research (CIHR).
