ISDN2014_0058: p63 and p73 coordinate p53 function to determine the balance between survival, cell death and senescence in adult neural precursor cells

Abstract

The p53 family members p73 and p63 have been implicated in various aspects of stem cell regulation. Here, we have asked whether they work together to regulate stem cell biology, focusing upon neural precursor cells (NPCs) in the adult murine brain. By studying mice that are haploinsufficient for p63 and/or p73, we show that these two proteins cooperate to ensure appropriate NPC self-renewal and long-term maintenance in the hippocampus and forebrain, and that when both are haploinsufficient, the NPC deficits are significantly greater than haploinsufficiency for either alone. We show that, in the case of p63 þ / À mice, this decrease in adult NPCs is caused by enhanced apoptosis. However, when p73 is coincidently haploinsufficient, this rescues the enhanced apoptosis of p63 þ / À NPCs under both basal conditions and following genotoxic stress, instead causing increased cellular senescence. This increase in cellular senescence is likely due, at least in part, to increased levels of basal DNA damage and p53 activation, as genetic ablation of p53 completely rescues the senescence phenotype observed in p63mice. Thus, the presence of p73 determines whether p63 þ / À NPCs exhibit increased p53-dependent apoptosis or senescence. Together, these studies demonstrate that p63 and p73 cooperate to maintain adult NPC pools through regulation of p53 function; p63 antagonizes p53 to promote cellular survival, whereas p73 regulates self-renewal and p53-mediated apoptosis versus senescence. Cell Death and Differentiation (2014) 21, 1546-1559; doi:10.1038/cdd.2014.61; published online 9 May 2014In the adult mammalian brain, new neurons are constantly being generated and integrated into pre-existing circuitry. These new neurons are generated by neural precursor cells (NPCs) that reside in two specialized niches-the subgranular zone (SGZ) of the dentate gyrus in the hippocampus, and the subventricular zone (SVZ) of the lateral ventricles.1,2 In the hippocampus, NPCs from the SGZ generate mature dentate granule neurons, which aid in the process of memory formation and consolidation. In the SVZ, neuroblasts migrate into the olfactory bulb, where they differentiate into interneurons that help regulate processes such as olfactory discrimination.Given these contributions to cognitive function, adult NPCs must be tightly regulated in terms of survival, proliferation, and self-renewal. Although many regulators of these processes have been found, very little is known about how they interact with one another to determine cellular status. One such group of regulatory proteins known to coordinate all the above processes in NPCs is the p53 family. Although studies have shown a plethora of interactions between p53 family members in both normal and pathological states, [3][4][5][6] no studies have been performed examining the functional interactions of all expressed family members in adult NPCs.The p53 family of transcription factors consists of p53, p63, and p73 with similar transactivation, DNA-binding, and oligomerization domains. For p63 and ...

Bcl‐2 is required for the survival of doublecortin‐expressing immature neurons

“…Our findings add to a growing number of recent papers examining how members of the Bcl‐2 family regulate adult NPCs. Mcl‐1 and p63 regulate the survival of dividing and postmitotic NPCs, whereas similar to our findings with Bcl‐2, others have shown that Bax, Bim, and PUMA regulate survival of postmitotic NPCs (Bunk et al, ; Sahay et al, ; Malone et al, ; Cancino et al, ; Fatt et al, ). In contrast, Bcl‐xL has no effect on regulation of adult neurogenesis in a naïve condition, whereas in the condition of ischemia it can promote survival (Doeppner et al, ).…”

“…For example, conditional deletion of Mcl‐1 in the adult brain suggests that Mcl‐1 is important in the survival of dividing NPCs (Malone et al, ), similar to its effects in embryonic development (Arbour et al, ). Similarly, p63 is also required for the survival of young NPCs and DCX‐expressing immature neurons and this effect is at least in part, attributed to silencing of the p53‐PUMA‐dependent death pathways (Cancino et al, ; Fatt et al, ). These findings suggest that these Bcl‐2 family members are required during both critical periods that regulate survival.…”

MicroRNA‐20a‐5p contributes to hepatic glycogen synthesis through targeting p63 to regulate p53 and PTEN expression

“…Fatt et al . found that p63 and p73 co‐regulated p53‐dependent neural precursor cell apoptosis versus senescence, whereby determining appropriate adult neurogenesis . The studies of p63 in more aggressive, metastatic tumours indicated that p63 loss accelerated tumour genesis as well as metastatic spread .…”

Immunocytochemical p63 expression discriminates between primary cutaneous follicle centre cell and diffuse large B cell lymphoma‐leg type, and is of the TAp63 isoform

“…TAp63α contains a sterile alpha motif (SAM) implicated in protein–protein interaction and may be a negative regulator of TAp63γ . In addition, mechanisms other than overexpression may contribute to the neoplastic nature of p63, as a complex interaction exists between transcriptional activators of the same family, namely p53 and p73, and this is likely to dictate tissue‐specific roles for p63 isoforms; for example, p63 can compensate for p53 in conditions of genotoxic stress, but may also antagonize p53, thereby promoting cell survival . Finally, although p63 is rarely mutated in malignancy, Yamaguchi et al .…”