24 May 2001

A study in the June issue of Nature Neuroscience points a finger at proteins of the Shc family as the critical link in signaling neural stem cells to either remain in their pluripotent form or differentiate into mature neurons. Italian researchers and their colleagues in France find that one form of the protein is expressed exclusively in stem cells, while another is expressed only in differentiated neurons.

The protein ShcA has been demonstrated to play a role in maintaining the immature and pluripotent state in stem cells. (It serves as a link between extracellular activation of protein tyrosine kinase receptors and the intracellular cascade, involving the Ras-MAPK pathway, that leads to cell division.) These researchers had previously determined that ShcA is selectively expressed in cells of the mitotically active germinal zone of embryonic brain, and that it is down-regulated as stem cells differentiate into neurons. In the present study, they find that ShcA is replaced by ShcC in differentiated neurons, and only in neurons. Through various manipulations of cells in culture, they show that ShcC is essential for the maturation and survival of neurons, whereas ShcA cannot rescue neurons depleted of ShcC. ShcC initiates this survival and maturation by recruiting the P13K-Akt-Bad pathway and persistent activation of the MAPK pathway.

The authors postulate that as a different Shc protein becomes available to pathways that transduce external developmental signals, a different set of proteins-those that are necessary for differentiation-can be expressed. They go so far as to suggest that "regulation of [ShcA and ShcC] availability during brain development may represent the key event that drives proliferation of differentiation signals." If this is true, critical questions include how this regulation occurs and how one might manipulate it in order to use stem cells to treat neurodegenerative disease.—Hakon Heimer