Red light, green light: U-M research offers new insight about how a stem cell becomes a neuron

ANN ARBOR — A team of scientists at the University of Michigan has identified a molecular switch that triggers a stem cell’s progeny to make a U-turn after cell division and commit to generating only differentiated cell types of the central nervous system, such as neurons and glial cells, by giving up its “stemness.”

“Understanding how the capacity of stem cell progeny becomes restricted is critical," says senior study author Cheng-Yu Lee, Ph.D., a faculty member of the U-M Life Sciences Institute. “In many cancers, it’s the cells that end up in a state of partial commitment that give rise to tumors. In order to come up with new ways to attack them when things are going wrong, we have to have a firm grasp on the processes when they’re working right.”

The new research, published Feb. 27 in Developmental Cell, was conducted in the relatively simple brains of fruit fly larvae and challenges aspects of the prevailing model of stem cell differentiation, says study first author Derek Janssens, Ph.D., a member of Lee’s lab.

Derek Janssens, Ph.D. and Cheng-Yu Lee, Ph.D.

“The strategy we describe is extremely well suited for the fast pace of development in higher organisms,” says Janssens. “The stem cells are basically held back from committing to generating differentiated cell types when this molecular switch is set at the 'off' position by what we call the repressor network. In less than two hours after cell division, the repressor network becomes dismantled, and allows the opposing activator network to rapidly set the molecular switch to the 'on' position in stem cell progeny initiating the commitment to generating differentiated cell types.”

“One can think of it like a traffic light," says Lee, who is also an associate professor of cell and developmental biology at the U-M Medical School. “The stem cell wants to turn green — to move forward on the commitment process — but is being held in check by the red light of the repressor network. In the stem cell, the green light program and the red light program are both trying to modify the same part of the genetic code, but the repressor network is able to block the activation of these critical differentiating genes. After cell division, the red light program is rapidly shut off in their daughter cell — giving them the green light to exit from stemness and continue on the journey of becoming a differentiated neuron.”

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Disclosure & Authorship

Additional authors include Danielle C. Hamm, Lucas Anhezini, Qi Xiao, Karsten H. Siller, Sarah E. Siegrist and Melissa M. Harrison.

The work was supported by the National Institutes for Health and the Cellular and Molecular Biology Ph.D. program at U-M.