p73 is dispensable for commitment to neural stem cell fate, but is essential for neural stem cell maintenance and for blocking premature differentiation

Alexandrova, Evguenia M.; Talos, Flaminia; Moll, Ute M.

doi:10.1038/cdd.2012.134

Cited by 15 publications

(21 citation statements)

References 8 publications

(16 reference statements)

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“…To investigate a possible role of the p53 homologs p63 and p73 in reprogramming, we transduced wild-type (WT) and corresponding null MEFs from littermate embryos with OSK. Consistent with previous results, [21][22][23][24][25][26][27][28][29] p53 À / À MEFs were reprogrammed with much higher efficiency compared with WT MEFs, while p73 deficiency did not affect reprogramming or pluripotency of established iPSC colonies, as we recently reported 34 (Supplementary Figures 1A, C-F). In striking contrast, reprogramming efficiency of p63 À / À MEFs was markedly reduced compared with WT controls (Figure 1a, Supplementary Figure 1B).…”

Section: Resultssupporting

confidence: 92%

“…However, whether and how p53 homologs p63 and p73 can regulate reprogramming was unknown. Using a loss-of-function approach, we show here and in a previous report 34 that p73 À / À MEFs reprogram normally and are fully pluripotent, indicating that p73 has no role in reprogramming. On the other hand, forced DNp73 overexpression was found to significantly improve speed and efficiency of reprogramming of human fibroblasts.…”

Section: Discussionsupporting

confidence: 51%

“…[35][36][37] p63 and p73 have been implicated in oncogenesis, [35][36][37] but their role in somatic reprogramming has barely been investigated. 34,38 Here we show for the first time that DNp63 is a potent positive regulator of reprogramming. Moreover, we show that different three-and two-factor reprogramming pathways have different p63 dependencies, providing evidence that reprogramming can proceed via multiple distinct routes.…”

mentioning

confidence: 71%

“…30,31 p73 KO mice exhibit defective embryonic and adult neurogenesis associated with hydrocephalus, cortical thinning and hippocampal dysgenesis. [32][33][34] Both p63 and p73 exist in multiple N-and C-terminal isoforms. Thus, full-length TAp63/TAp73, which carry the N-terminal transcriptional activation (TA) domain, can induce cell cycle arrest and apoptosis similar to p53, whereas the N-terminally truncated DNp63/DNp73 often act in a dominant-negative manner by inhibiting full-length family members, including p53.…”

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confidence: 99%

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ΔNp63 regulates select routes of reprogramming via multiple mechanisms

Petrenko

Nemajerová

et al. 2013

Cell Death Differ

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Somatic cells can be converted into induced pluripotent stem cells (iPSCs) by forced expression of various combinations of transcription factors, but the molecular mechanisms of reprogramming are poorly understood. Specifically, evidence that the reprogramming process can take many distinct routes only begins to emerge. It is definitively established that p53 deficiency greatly enhances reprogramming, revealing p53's barrier function for induced pluripotency, but the role of its homologs p63 and p73 are unknown. Here we report that in stark contrast to p53, p73 has no role in reprogramming. However, p63 is an enabling (rather than a barrier) factor for Oct4, Sox2 and Klf4 (OSK) and Oct4 and Sox2 (OS), but not for Oct4 and Klf4 (OK) reprogramming of mouse embryonic fibroblasts. Specifically, p63 is essential during reprogramming for maximum efficiency, albeit not for the ability to reprogram per se, and is dispensable for maintaining stability and pluripotency of established iPSC colonies. DNp63, but not TAp63, is the principal isoform involved. Loss of p63 can affect reprogramming via several mechanisms such as reduced expression of mesenchymal-epithelial transition and pluripotency genes, hypoproliferation and loss of the most reprogrammable cell populations. During OSK and OS reprogramming, different mechanisms seem to be critical, such as regulation of epithelial and pluripotency genes in OSK reprogramming versus regulation of proliferation in OS reprogramming. Finally, our data reveal three different routes of reprogramming by OSK, OS or OK, based on their differential p63 requirements for iPSC efficiency and pluripotency marker expression. This supports the concept that many distinct routes of reprogramming exist.

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Section: Resultssupporting

confidence: 92%

Section: Discussionsupporting

confidence: 51%

mentioning

confidence: 71%

mentioning

confidence: 99%

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ΔNp63 regulates select routes of reprogramming via multiple mechanisms

Petrenko

Nemajerová

et al. 2013

Cell Death Differ

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“…Clearly, since p73 is a transcription factor, the phenotype observed in p73-/-mice is in part linked to regulation of gene expression. Indeed, several genes that are involved in neuronal biology, such as, SOX-2 [27], Hey-2 [28], TRIM32 [29] and p75NTR [30], are either directly or indirectly regulated by TAp73 [31][32][33][34][35]. In addition, TAp73 controls the expression of miR-34a, suggesting that microRNAs [36,26] also participate in the multifunctional role of p73 in neurons, such as differentiation [26].…”

Section: Introductionmentioning

confidence: 99%

p73 Regulates Primary Cortical Neuron Metabolism: a Global Metabolic Profile

Agostini

Niklison-Chirou

Annicchiarico-Petruzzelli

et al. 2017

Mol Neurobiol

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How Does p73 Cause Neuronal Defects?

et al. 2015

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The p53-family member, p73, plays a key role in the development of the central nervous system (CNS), in senescence, and in tumor formation. The role of p73 in neuronal differentiation is complex and involves several downstream pathways. Indeed, in the last few years, we have learnt that TAp73 directly or indirectly regulates several genes involved in neural biology. In particular, TAp73 is involved in the maintenance of neural stem/progenitor cell self-renewal and differentiation throughout the regulation of SOX-2, Hey-2, TRIM32 and Notch. In addition, TAp73 is also implicated in the regulation of the differentiation and function of postmitotic neurons by regulating the expression of p75NTR and GLS2 (glutamine metabolism). Further still, the regulation of miR-34a by TAp73 indicates that microRNAs can also participate in this multifunctional role of p73 in adult brain physiology. However, contradictory results still exist in the relationship between p73 and brain disorders, and this remains an important area for further investigation.

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p73 is dispensable for commitment to neural stem cell fate, but is essential for neural stem cell maintenance and for blocking premature differentiation

Cited by 15 publications

References 8 publications

ΔNp63 regulates select routes of reprogramming via multiple mechanisms

ΔNp63 regulates select routes of reprogramming via multiple mechanisms

p73 Regulates Primary Cortical Neuron Metabolism: a Global Metabolic Profile

How Does p73 Cause Neuronal Defects?

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