Broad Center Scientists Discover Pathway that Controls Neural Stem Cells

A neuroscientist and his coworkers at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA have published a major findings in the control of nerve cell regeneration. Nerve cells arise from neural stem cells (NSCs), and NSCs can divide and form neurons, the conductive cells in the nervous system, or glial cells, which act as support cells. What are the triggers that cause NSCs to form one or the other?

A research team at UCLA led by Bennett Novitch, assistant professor of neurobiology, has found some answers to this question. According to Novitch, ““One of the greatest mysteries in developmental biology is what constitutes the switch between stem cell proliferation and differentiation. In our studies of the formation of motor neurons — the cells that are essential for movement — we were able to uncover what controls the early expansion of neural stem and progenitor cells, and more importantly, what stops their proliferation when there are enough precursors built up. If the neurons don’t form at the proper time, it could lead to deficits in their numbers and to catastrophic, potentially fatal neurological defects.”

Novitvh’s laboratory has shown that a finely-tuned network of gene expression drives the NSCs to initially divide and then cease dividing and differentiate into neurons and other types of nerve cells.

During the 12 weeks of development (the first trimester), NSCs and progenitor cells that are programmed to make specific nerve cells for a specific zone where the cells stick tightly to each other. This adhesion is medicated by a molecule called “N-Cadherin.” By sticking to each other, the cells expand without differentiating into nerve cells. Once the time comes for cells to motor neurons (those neurons that direct skeletal muscles to contract and move parts of the skeleton), two proteins, Foxp2 and Foxp4, increase in concentration and shut off N-Cadherin expression. The cessation of N-Cadherin expression causes the NSCs to break apart and initiate differentiation.

Novitch explained further, ““We have these cells in a dividing state, making more of themselves. And to make neurons, that process has to be stopped and those contacts between the cells disassembled. Until now, it has not been clear how the cells are pulled apart.”

Elimination of Foxp protein function prevents the normal formation of motor neurons and other mature cells in the nervous system. NSCs that lack Foxp, do not show downregulation of N-cadherin gene. This illustrates the fine tuning of gene expression that is necessary for the normal development of the nervous system.

Novitch discussed the significance of his group’s findings further, ““It’s a fundamental discovery. Most studies have focused on defining what promotes the adhesiveness and self-renewal of neural stem cells, rather than what breaks these contacts. We were also surprised to see how small changes in the degree of cell adhesion can markedly alter the development and structure of the nervous system. It’s all about balance — if you have too many or too few stem and precursor cells, the result could be disastrous.”

Another possible role for the Fox proteins is in cancer, since the inability of cells to exit the cell cycle and differentiate could cause them to divide uncontrollably and accumulate mutations that cause them to grow faster and faster. Alternatively, the Fox proteins might also play a central part in establishing neural networks that development abnormally in patients with cognitive or speech-acquisition disabilities.