Stem cells (left) and differentiated neurons (right) visualized by immunofluorescence; the expression of ShcA and ShcC is balanced in these cell populations. Courtesy of Elena Cattaneo, University of Milan, Italy.

The finding of neuronal stem cells in the adult brain has pointed to new avenues of treatment for neurodegenerative diseases and traumatic brain injury. But realizing the clinical potential of this knowledge will depend on an understanding of the molecular mechanisms that control the fate of stem cells in the central nervous system. How is the switch from immature stem cell to mature neuron achieved? Conti and colleagues have taken an important step towards answering this question by showing that changes in the expression of Shc adaptor proteins occur as cells undergo neuronal differentiation.

Shc proteins couple activated protein tyrosine kinase receptors to downstream signalling pathways, allowing cells to respond to trophic agents such as nerve growth factor. As they report in Nature Neuroscience, Conti et al. showed that neuronal precursors differ from mature neurons in their expression of two forms of Shc. So, whereas neuronal stem/progenitor cells express ShcA, they were found to be largely devoid of ShcC. Conversely, ShcC was expressed at relatively high levels in the mature brain, unlike ShcA, which was downregulated as development progressed. In fact, ShcC was expressed only in post-mitotic neurons, apparently replacing ShcA, and its level of expression increased with brain maturation.

Conti et al. went on to show that ShcA, expressed in cultured neuronal progenitors, and ShcC, expressed in these cells as they differentiated, could be activated equally by the same ligands; but whereas the former supports the proliferation of neuronal precursors, ShcC was found to activate pathways that promote the survival and differentiation of post-mitotic neurons. These data indicate that the switch from ShcA to ShcC drives the transformation of progenitor cells into fully functional neurons. But what causes this shift in expression? Finding the answer to this question could be the next step in our efforts to harness the therapeutic potential of neuronal stem cells.