Early in embryonic development, the neural crest – a transient group of stem cells – gives rise to parts of the nervous system and several other tissues. But what determines which cells become neurons and which become other cell types? It turns out a gene called SOX2acts as a stem cell gatekeeper – only cells expressing it have the potential to become neurons.

The SOX2 gene encodes a transcription factor, a type of protein that switches other genes on or off. SOX2 is one of two key genes researchers use to generate induced pluripotent stem cells (iPSCs), which are capable of differentiating into all cell types for research and potential therapeutic applications.

In a paper published May 5 in the journal Cell Stem Cell, Drs. Alexey Terskikh, Flavio Cimadamore and colleagues show that SOX2 maintains the potential for neural crest stem cells to become neurons in the peripheral nervous system, where they interface with muscles and other organs. These results could help better inform therapies aimed at neurocristopathies, diseases caused by defects in the neural crest, which include microphthalmia and CHARGE syndrome.

According to Dr. Cimadamore, post-doctoral researcher and first author of the study, “Neural crest cells are notoriously difficult to study in humans because of their very early and transient nature – a woman is usually not even yet aware of her pregnancy when they start to migrate and differentiate. So here we took advantage of an embryonic stem cell-based model of human neural crest previously developed in our lab to get a better understanding of the molecular pathways that control the differentiation potential of such cells in humans.”

Using this new neural crest model, the researchers showed that stem cells in the developing nervous system start out with SOX2, but lose it at the stage when they are considered migratory neural crest cells. Later, as neural crest stem cells aggregate at a subsequent point in development, SOX2 is regained only by those cells fated to become neurons. Neural crest stem cells that remain SOX2-free differentiate into other cell types, but never become neurons.

To determine how SOX2 controls this stage in nervous system development, the researchers looked at the genes it acts upon. They found that SOX2 switches on neurogenin-1 and Mash-1, two genes that support neuronal survival in both the central and peripheral nervous systems.

“If we prevent neural crest stem cells from re-expressing SOX2, we don’t get neurons. If we try to push these SOX2-deficient cells to become neurons, they die, but they can readily give rise to glia or smooth muscle cells,” says Dr. Terskikh, assistant professor in Sanford-Burnham’s Development and Aging Program and senior author of the study. “We think that one function of SOX2 is to keep cells multipotent or pluripotent for one reason – if they need to become a neuron later in development. We hope this finding will be useful to researchers studying neural crest development and stem cell differentiation.”

###
Original paper:
Cimadamore F, Fishwick K, Giusto E, Gnedeva K, Cattarossi G, Miller A, Pluchino S, Brill LM, Bronner-Fraser M, & Terskikh AV (2011). Human ESC-Derived Neural Crest Model Reveals a Key Role for SOX2 in Sensory Neurogenesis. Cell Stem Cell, 8 (5), 538-551 : doi:10.1016/j.stem.2011.03.011