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connected to cell cycle exit. It is also tempting to speculate that neurons that
have already exited the cell cycle might be driven to go backward in the dif-
ferentiation process and to resume their plastic potential reexpressing cell cy-
cle proteins. According to this view, neurons that are able to resume a
genetic program that induces neurite outgrowth should be considered as
“less differentiated” compared to postmitotic neurons. This concept might
have important implications for axonal regeneration of CNS neurons fol-
lowing injury considering the idea that postmitotic neurons might be pushed
to switch from a quiescent into a pro-growth mode by reentering the cell
cycle program.
Along the same lines, control of cell cycle entry and length is also very
important for reprogramming of differentiated cells into induced pluripotent
stem (iPS) cells. Indeed, pluripotent stem cells including embryonic stem
cells and iPS cells share a distinctive and peculiar feature being both charac-
terized by a short cell cycle with an abbreviated G
1
phase of only 2-3 h
(
Ghule et al., 2011
). Importantly, in this context, p53 appears to behave
as a gatekeeper between pluripotency and differentiation almost functioning
as a “reprogramming barrier” to ensure iPS cells' genome integrity (
Marion
et al., 2009
).
Although p53 may work as a cell cycle gatekeeper in different cell types
and biological processes, there is mounting evidence that distinct PTMs and
cofactors that fine-tune p53 activity, triggering different transcriptional
pathways and cellular responses in postmitotic neurons, may signal via
mechanisms independent of cell cycle regulation.
Given that neural stem cell polarity, self-renewal, proliferation, and dif-
ferentiation are tightly regulated by epigenetic modifications that affect the
cellular clock, it may be interesting to study the cross talk between epige-
netic modifications and p53 PTMs in this context. Other interesting open
questions regard the cross-signaling between p53 and other transcriptional
partners in the context of both axonal regeneration and neurogenesis.
A deeper understanding of the complex regulation of p53, as a regulator
of both axonal regeneration and neurogenesis, might help in designing phar-
macological and genetic strategies to promote neuronal repair and regener-
ation following CNS trauma.
ACKNOWLEDGMENTS
This work was supported by funds granted by the Hertie Foundation; the Center for
Integrative Neuroscience (CIN), Tuebingen; the Fort¨ne Program, University of
Tuebingen; the DFG (all granted to Simone Di Giovanni).
