Biology Reference
In-Depth Information
apoptosis is key for the establishment of the correct neuronal connections
(
Buss &Oppenheim, 2004
), the mechanism by which neurons integrate dif-
ferent apoptotic stimuli such as neurotrophic withdrawal, oxidative stress, or
DNA damage is still elusive. Interestingly, p53 absence is able to rescue the
massive apoptotic phenotype exhibited by DNA ligase 4, pRb, and XRCC4
mutant mice (
Frank et al., 2000; Gao et al., 2000; Macleod, Hu, & Jacks,
1996
), suggesting p53 as crucial convergent checkpoint in the elimination
of newborn neurons
that are not
selected for differentiation and
integration by the preexisting network.
In agreement with these findings, in the developing peripheral nervous
system, p53 is required for the apoptosis of sympathetic neurons that do not
receive neurotrophic support due to the limiting quantity of NGF available
in the system (
Miller & Kaplan, 2001; Vogel & Parada, 1998
).
In addition to its role in neuron survival during development, p53 seems
also to be a key regulator of embryonic and adult neural stem cells self-
renewal and differentiation. Indeed, p53 is expressed in proliferating and
early differentiating progenitor cells in the embryonic and adult rodent brain
(
Meletis et al., 2006; van Lookeren Campagne & Gill, 1998
).
Despite an extensive body of literature aimed at elucidating the role of
p53 in neural stem cells regulation, the exact molecular nature of its contri-
bution has not been fully clarified.
One of the distinctive features that characterizes and distinguishes neu-
roblasts from quiescent stem cells is their proliferative ability and therefore
their cell cycle length. Neuroblasts are characterized by a shorter cell cycle
and proliferate by symmetric division to expand quickly their own pool; on
the other side, quiescent slow-cycling stem cells keep a very low metabolic
rate but, at the same time, prevent depletion of the precursor pool. In this
scenario, cell cycle inhibitors such as p53 and p21 play a crucial role since
their deletion may lead to exhaustion of the neural precursor pool. Indeed,
in the adult SVZ, p53 deletion increases proliferation and survival of neural
stem cells, but this alteration in their proliferative ability is not sufficient to
induce tumor formation. Furthermore, in the embryonic olfactory bulb, the
absence of p53 is associated with an increase in proliferation rate and neu-
ronal differentiation of neurospheres, although it also decreases their chro-
mosomal stability (
Armesilla-Diaz et al., 2009; Gil-Perotin et al., 2006;
Meletis et al., 2006
). In line with this finding, p21 deletion increases
neural progenitor proliferation, causing their exhaustion (
Kippin,
Martens, & van der Kooy, 2005
), and upon stroke injury, it increases
their proliferation, migration, and differentiation (
Qiu et al., 2004
).
