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
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
Reference:Conti L, Sipione S, Magrassi L, Bonfanti L, Rigamonti D, Pettirossi V, Peschanski M, Haddad B, Pelicci P, Milanesi G, Pelicci G, Cattaneo E.
Shc signaling in differentiating neural progenitor cells.
Nat Neurosci. 2001 Jun;4(6):579-86. Abstract