p63 Antagonizes p53 to Promote the Survival of Embryonic Neural Precursor Cells

Dugani, Chandrasagar B.; Paquin, Annie; Fujitani, Masashi; Kaplan, David R.; Miller, Freda D.

doi:10.1523/jneurosci.5878-08.2009

Cited by 39 publications

(57 citation statements)

References 64 publications

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“…Overexpression of TAp73 also increases spontaneous differentiation of oligodendrocytes from precursor cells (6), and its role in differentiation of the nervous system may therefore not be confined to neurons (5). In contrast, ΔNp73 has been shown to act together with ΔNp63 in regulating the survival of cortical precursor cells (21), and both p73 +/− and selective ΔNp73 −/− mice are more susceptible to neurodegeneration (22,23).…”

Section: Resultsmentioning

confidence: 99%

Neuronal differentiation by TAp73 is mediated by microRNA-34a regulation of synaptic protein targets

Agostini

Tucci

Killick

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

167

146

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The p53-family member TAp73 is a transcription factor that plays a key role in many biological processes. Here, we show that p73 drives the expression of microRNA (miR)-34a, but not miR-34b and -c, by acting on specific binding sites on the miR-34a promoter. Expression of miR-34a is modulated in parallel with that of TAp73 during in vitro differentiation of neuroblastoma cells and cortical neurons. Retinoid-driven neuroblastoma differentiation is inhibited by knockdown of either p73 or miR-34a. Transcript expression of miR-34a is significantly reduced in vivo both in the cortex and hippocampus of p73 −/− mice; miR-34a and TAp73 expression also increase during postnatal development of the brain and cerebellum when synaptogenesis occurs. Accordingly, overexpression or silencing of miR-34a inversely modulates expression of synaptic targets, including synaptotagmin-1 and syntaxin-1A. Notably, the axis TAp73/miR-34a/synaptotagmin-1 is conserved in brains from Alzheimer's patients. These data reinforce a role for TAp73 in neuronal development.cell death | neurodegeneration | Alzheimer disease T he p53-family member Trp73 is transcribed from two distinct promoters, resulting in isoforms containing or lacking the Nterminal TA domain, known as TAp73 (1, 2) and ΔNp73 (3), respectively; additionally, alternative 3′-splicing produces further variants (α, β, and so forth). In keeping with their sequence and structural similarities, TAp73 can mimic several p53 functions, including the transactivation of p21, Puma, and Bax, although p73 also has distinct transcriptional targets. Indeed, p73 −/− mice show developmental defects of the CNS; for example, congenital hydrocephalus, hippocampal dysgenesis, and defects of pheromone detection rather than the enhanced tumor susceptibility of p53 −/− mice (4). This development is not simply because of apoptosis, as the ectopic expression of p73 induces neurite outgrowth and expression of neuronal markers in neuroblastoma cell lines (5) and in primary oligodendrocytes (6).Several microRNAs (miRs) are regulated by p53 (7), although p73-dependent miRs have been less well studied. In particular, the miR-34 family (miR-34a to -c) has been shown to be a direct target of p53 (8-10). Ectopic expression of miR-34 mimics several p53 effects, although in a cell type-specific manner. In mice, miR-34a is ubiquitous with the highest expression in brain, and overexpression of miR-34a in neuroblastoma cell lines modulates neuronal-specific genes (11); miR-34b and -c are mainly in the lung (12).Because both p73 and miRs, including miR-34a, have been implicated in neuronal differentiation, we have investigated the possibility that p73 drives miR-34a expression using WT and p73-null mice. We demonstrate that miR-34a is transcriptionally regulated by TAp73 and that, in turn, miR-34a regulates the expression of a number of synaptic proteins, in particular synaptotagmin I and syntaxin 1A in cortical neurons. Moreover, neuronal architecture is disorganized in p73-null mice, and manipulation of miR-34a expressi...

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Section: Resultsmentioning

confidence: 99%

Neuronal differentiation by TAp73 is mediated by microRNA-34a regulation of synaptic protein targets

Agostini

Tucci

Killick

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

167

146

View full text Add to dashboard Cite

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“…CD1 mice, purchased from Charles River Laboratory, were used for all culture and electroporation experiments. Sox2: EGFP mice (Ellis et al, 2004) maintained on a C57BL/6 background were used for sorting experiments and were genotyped and maintained as described previously (Biernaskie et al, 2009). Mice and embryos of both sexes were used.…”

Section: Methodsmentioning

confidence: 99%

“…E13 littermate embryos were harvested from crosses between Sox2:EGFP and wild-type C57BL/6 mice. EGFP-positive and -negative animals were separated, and cortical cells were harvested as described for the culture experiments, dissociated to single cells in 1% BSA, and sorted for EGFP expression on a MoFlo fluorescent activated cell sorter (Dako) with viable cells identified by propidium iodide exclusion as previously described (Biernaskie et al, 2009). Gates were set using cells isolated from the EGFP-negative cortices.…”

Section: Methodsmentioning

confidence: 99%

Snail Coordinately Regulates Downstream Pathways to Control Multiple Aspects of Mammalian Neural Precursor Development

et al. 2014

Self Cite

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The Snail transcription factor plays a key role in regulating diverse developmental processes but is not thought to play a role in mammalian neural precursors. Here, we have examined radial glial precursor cells of the embryonic murine cortex and demonstrate that Snail regulates their survival, self-renewal, and differentiation into intermediate progenitors and neurons via two distinct and separable target pathways. First, Snail promotes cell survival by antagonizing a p53-dependent death pathway because coincident p53 knockdown rescues survival deficits caused by Snail knockdown. Second, we show that the cell cycle phosphatase Cdc25b is regulated by Snail in radial precursors and that Cdc25b coexpression is sufficient to rescue the decreased radial precursor proliferation and differentiation observed upon Snail knockdown. Thus, Snail acts via p53 and Cdc25b to coordinately regulate multiple aspects of mammalian embryonic neural precursor biology.

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“…Cortical precursor cells were cultured as previously described [16,[18][19][20]. amplified product size-448 bp).…”

Section: Cell Culture and Reagentsmentioning

confidence: 99%

“…Immunocytochemistry of cultured cells and tissue sections was performed as described [16,19,20]. (Figure 1).…”

Section: Immunocytochemistrymentioning

confidence: 99%

Neuropathogenesis of Noonan syndrome is mediated by inflammatory microglia

Antony

2011

Translational Neuroscience

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Microglia are resident hematopoietic cells that play important roles in the damaged or degenerating adult nervous system. Microglia are involved in neuropathogenesis of various diseases. Microglia are also essential for neuroprotection and comprise an essential component of the neural stem cell niche. The activation of microglia is an important phenomenon associated with several neurological disorders that arise from infections to developmental abnormalities and behavioral pathologies. Noonan syndrome (NS) is associated with mutations in the PTPN11 gene and also accounts for mental retardation in children. Interestingly, in mouse models of NS, mutations in the PTPN11 gene resulted in dysregulation of neural progenitors. The present study describes the activation of microglia in the NS mouse model, which results in an inflammatory phenotype with expression of IL-1b and defective phagocytosis. To test whether microglia from NS mice are important for neural precursor maintenance or self-renewal, embryonic neural precursors from the cortex of WT mice were cultured. Microglia from NS and WT mice were then added to cortical precursor cells which showed that microglia from NS mice inhibited astrogenesis. Together, these results demonstrate that microglia can dysregulate neural precursor development in NS, and suggest that alterations in microglial number as a consequence of genetic or pathological events may perturb neural development by directly affecting embryonic neural precursors.

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p63 Antagonizes p53 to Promote the Survival of Embryonic Neural Precursor Cells

Cited by 39 publications

References 64 publications

Neuronal differentiation by TAp73 is mediated by microRNA-34a regulation of synaptic protein targets

Neuronal differentiation by TAp73 is mediated by microRNA-34a regulation of synaptic protein targets

Snail Coordinately Regulates Downstream Pathways to Control Multiple Aspects of Mammalian Neural Precursor Development

Neuropathogenesis of Noonan syndrome is mediated by inflammatory microglia

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