How Neural Stem Cells Create New and Varied Neurons

A new study in fruit flies has elucidated a mechanism in neural stem cells by which these types of stem cells generate the wide range of neurons that they form.

Chris Doe, a professor of biology from the Institute of Neuroscience at the University of Oregon, and his co-authors have used the common fruit fly Drosophila melanogaster to investigate the cellular mechanism by which neural stem cells make their distinctive progeny.

As Doe put it, “The question we confronted was ‘How does a single kind of stem cell, like a neural stem cell, make all kinds of neurons?”

Researchers have known for some period of time that stem cells have the capacity to produce new cells, but the study by Doe’s group shows how a select group of stem cells can create progenitor cells that can generate numerous subtypes of cells.

Doe’s study builds on previous studies in which Doe and his colleagues identified the specific set of stem cells that generated neural precursors. These so-called “intermediate neural progenitors” or INPs can expand to form several different new cell types. However, this study did not account for the diversity of the cells generated even if it did account for the number of cells generated (see Boone JQ, Doe CQ, Dev Neurobiol. 2008 Aug;68(9):1185-95).

“While it’s been known that individual neural stem cells or progenitors could change over time to make different types of neurons and other types of cells in the nervous system, the full extent of this temporal patterning had not been described for large neural stem cell lineages, which contain several different kinds of neural progenitors,” according to this study’s first author Omar Bayraktar.

The cell types discovered in this study have analogs in the developing human brain and the research has potential applications for human biologists who want to know how neurons form in the human brain.

The paper from Doe’s lab was published along another study on the generation of diverse neurons by a group from New York University. These two papers provide new insight into the means by which neural stem cells generate the wide range of neurons found in the brains of fruit flies and humans.

In their study, Bayraktar and Doe specifically examined stem cells in fruit fly brains known as type II neuroblasts, which generate INPs. However, in this study, the type II neuroblasts were shown to generate INPs, which then go on to form distinct neural subtypes. Even though previous work showed that INPs went on to form about 100 new neurons, in this paper, the INPs were shown to make about 400-500 new neurons.

Another interesting finding was that the gene expression patterns of INPs, which began with three different transcription factors (Dichaete, Grainy Head, and Eyeless). These transcription factors lay the groundwork for INP differentiation, but once INP formation occurs, a new transcriptional program is extended that extends the types of neurons that INPs can form. Such nested transcriptional programs are also common during the specification of neural stem cell progeny in humans brains, with many of the same transcription factors playing a central role in neuron specification.

“If human biologists understand how the different types of neurons are made, if we can tell them ‘This is the pathway by which x, y, and Z neurons are made,’ then they may be able to reprogram and redirect stem cells to make these precise neurons,” Doe said.

However, the mechanism described in this paper has its limits. Eventually the process of generation new cells stops. One of the next questions to answer will be what makes the mechanism turn off, according to Doe.

“This vital research will no doubt capture the attention of human biologists,” said Kimberly Andrews Espy, who is vice-president for research and innovation and the dean of the UP graduate school. “Researchers at the University of Oregon continue to further our understanding of the processes that undergird development to improve the health and well-being of people throughout the world.”

See Bayraktar OA, Doe CQ. Combinatorial temporal patterning in progenitors expands neural diversity. Nature. 2013 Jun 27;498(7455):449-55. doi: 10.1038/nature12266.