p73 Is Required for Survival and Maintenance of CNS Neurons

Abstract

Here, we show that the p53 family member, p73, is necessary for survival and long-term maintenance of CNS neurons, including postnatal cortical neurons. In p73-/- animals, cortical neuron number is normal at birth but decreases significantly by postnatal day 14 (P14)-P16 because of enhanced apoptosis. This decrease continues into adulthood, when p73-/- animals have approximately one-half as many cortical cells as their wild-type littermates. Cortical neurons express the DeltaNp73alpha protein, and overexpression of DeltaNp73 isoforms rescues cortical neurons from diverse apoptotic stimuli. Thus, DeltaNp73 isoforms are survival proteins in cortical neurons, and their deletion causes a gradual loss of cortical neurons in the weeks and months after birth. This decrease in CNS neuron number in p73-/- animals is not limited to the cortex; facial motor neuron number is decreased, and postnatal development of the olfactory bulb is greatly perturbed. These findings, together with our previous work showing that DeltaNp73 is essential for survival of peripheral sympathetic neurons (Pozniak et al., 2000), indicate that p73 isoforms are essential survival proteins in CNS as well as PNS neurons, and that they likely play a role not only during developmental cell death but also in the long-term maintenance of at least some adult neurons.

p63 Overexpression Induces the Expression of Sonic Hedgehog

“…Like p63, p73 also exists as TA and DN isoforms based on promoter usage and alternate COOH-terminal splicing. p73 knockout mice exhibit defects in neuronal development (19,20).…”

Kinase activity-independent suppression of p73α by AMP-activated kinase α (AMPKα)

“…Therefore, we propose a common theme between AMPK-induced p53 activation and AMPKmediated p73a repression in promoting cellular survival in response to glucose deprivation and DNA damage, respectively. Both AMPK and p73 are implicated in neurodevelopment and neuronal survival in response to various stresses (Pozniak et al, 2000(Pozniak et al, , 2002Culmsee et al, 2001). In this respect, our observations may be of significance to determine whether AMPKa regulates neuronal survival by cooperating with p73a in response to death signals in the brain.…”

p73: regulator in cancer and neural development

“…For sympathetic neurons, this developmental apoptosis is partially dependent upon p53, and the same process will occur in a culture dish if these neurons are deprived of nerve growth factor or NGF. What Pozniak et al 28 found in this system was that neurons that would normally survive the developmental apoptosis period instead died in the p73À/À mice. In cultured wild-type sympathetic neurons, NGF caused a dramatic increase in DNp73 levels, which presumably antagonized the apoptotic actions of p53 and promoted survival.…”

“…In particular, examination of the p73À/À mouse revealed that it does not develop tumors, but instead has significant neurological abnormalities including enlarged ventricles, hippocampal dysgenesis, abnormalities in pheromone-sensory pathways 27 and loss of peripheral sympathetic neurons. 28 Interestingly, most of these phenotypes can be explained by either the absence or loss of neurons; the hippocampal phenotype was associated with the absence of neurons (Cajal-Retzius cells) important for development, the olfactory/pheromone phenotype was associated with the coincident absence of peripheral olfactory neurons, 27 and the p73À/À animals displayed enhanced loss of both PNS and CNS neurons postnatally. 28,29 Somewhat unexpectedly, DNp73 was the predominant isoform of p73 expressed in the murine fetal nervous system, leading to the conclusion that the neurological abnormalities in the p73À/À mice must be due to loss of the antiapoptotic form of p73.…”

“…A careful analysis of some of these p73À/À phenotypes provided possible explanations. Pozniak et al 28,29 examined the sympathetic ganglia and cortex of the p73À/À animals, and demonstrated that in both of these systems the loss of DNp73, the predominant isoform, led to enhanced neuronal apoptosis, leading them to conclude that this antiapoptotic p73 isoform is necessary for survival and long-term maintenance of both CNS and PNS neurons. Clues as to the underlying mechanism(s) came largely from their studies of peripheral sympathetic neurons, where the enhanced neuronal apoptosis was largely developmental.…”