Here’s a highlight summarizing three new papers.
Neural stem cells continuously form new neurons in the adult brain. But after injury, these stem cells seem able to become other cell types, such as glial cells that support neurons. This flexibility helps the brain heal naturally, but it poses a problem because researchers developing treatments for neurological diseases want to be able to direct cells to desired fates. In some diseases only new neurons are needed; for others the non-neuronal cells are essential. In a series of recent papers, two La Jolla, California, research groups provide potential solutions to these brain-bending problems, showing that overexpression of single genes can reliably direct neural differentiation.
Stuart Lipton and his colleagues at the Burnham Institute for Medical Research focused on creating pure cultures of neuronal cells. They genetically engineered mouse embryonic stem cells to constitutively express the transcription factor myocyte enhancer factor 2C (MEF2C), named after its role in muscle. They also used neuronal markers and electrophysiology to show, both in vitro and in vivo, that the transformed cell lines differentiated almost exclusively as neurons. After transplanting the cells into the brain, the researchers noticed that MEF2C also seemed to protect the cells from apoptosis. No tumours formed, and stroke-afflicted mice displayed improved performance in a suite of neurobehavioral tests1.
“The real beauty of this factor is we get two for one,” says Lipton, referring to both the neuronal induction and antiapoptotic properties of MEF2C. In a companion paper Lipton’s group showed the centrality of MEF2C in neuronal development by conditionally knocking out the MEF2C gene in neuronal stem (NS) cells during early mouse development2. This led to compacted, aggregated neurons with an abnormal distribution in the neocortex. Further, mice surviving to adulthood exhibited severe behavioural defects reminiscent of Rett syndrome, an autism-spectrum disorder2. Lipton thinks MEF2C has an underappreciated effect in the brain. “We think we’ve found the mother or father factor of what controls neural stem cells,” he says.
Still, other transcription factors are also important in neural development. Fred Gage, of the Salk Institute, and his colleagues concentrated on the transcription factor Ascl1. But rather than generating neuronal cells, Gage’s team coaxed NS cells that would ordinarily produce neurons to adopt a different neural cell fate. The team used retroviruses to induce overexpression of Ascl1 in adult mouse brains, which then redirected hippocampal NS cells to exclusively form oligodendrocytes, a type of glial cell that constitutes part of the myelin3. At a basic level, this confirms in vivo that certain adult NS cells deemed destined to form neurons actually retain fate plasticity, says Sebastian Jessberger, lead author of the study and now at the Swiss Federal Institute of Technology (ETH) in Zurich. On a more applied front, “it’s a proof of principle that you can tailor cell types” to any neural cell of interest, he says.
Daniel Hoeppner, of the National Institutes of Health’s National Institute of Neurological Disorders and Stroke, in Bethesda, Maryland, says that these papers “begin to break down the concept of [cell fate] commitment.” Lipton’s embryonic stem cells and Gage’s adult hippocampal stem cells are at opposite ends of the specificity spectrum, he notes, but simple manipulations dramatically change the output of both cell types. “These papers can provide the foundation for understanding the switch mechanisms in the cell that make it either specified or unspecified.” Both studies convincingly presented the genetic control underlying this switch, and the phenotypic characterizations were “robust and complete,” adds Hoeppner, but the molecular changes in gene expression and chromatin restructuring that accompany the reprogramming remain poorly described. Once those are also worked out, however, reprogramming NS cells could become a no-brainer.
1. Li, Z. et al. Myocyte enhancer factor 2C as a neurogenic and antiapoptotic transcription factor in murine embryonic stem cells. J. Neurosci. 28, 6557–6568 (2008).
2. Li, H. et al. Transcription factor MEF2C influences neural stem/progenitor cell differentiation and maturation in vivo. Proc. Natl. Acad. Sci. USA DOI: 10.1073/pnas.0802876105, AOP: 30 June 08
3. Jessberger, S. et al. Directed differentiation of hippocampal stem/progenitor cells in the adult brain, Nature Neurosci. advance online publication, doi:10.1038/nn.2148 (29 June 2008).
Elie Dolgin is a Canadian science writer currently residing in Milwaukee, Wisconsin.