CCAAT/Enhancer-Binding Protein Phosphorylation Biases Cortical Precursors to Generate Neurons Rather Than Astrocytes<i>In Vivo</i>

Paquin, Annie; Barnabé-Heider, Fanie; Kageyama, Ryoichiro; Miller, Freda D.

doi:10.1523/jneurosci.2662-05.2005

Cited by 76 publications

(88 citation statements)

References 61 publications

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“…4), indicating that ERK2 may be required for regulation of astrogliosis. This is consistent with previous reports, which demonstrated that inhibition of the MEK-ERK pathway resulted in enhanced generation of astrocytes (Paquin et al, 2005;Samuels et al, 2008;Heffron et al, 2009). GFAP ϩ cells seem to be more abundant in outer layers than inner layers of cortices (Fig.…”

Section: Generation Of Erk2 Cko Micesupporting

confidence: 93%

ERK2 Contributes to the Control of Social Behaviors in Mice

et al. 2011

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Signaling through extracellular signal-regulated kinase (ERK) is important in multiple signal transduction networks in the CNS. However, the specific role of ERK2 in in vivo brain functions is not fully understood. Here we show that ERK2 play a critical role in regulating social behaviors as well as cognitive and emotional behaviors in mice. To study the brain function of ERK2, we used a conditional, region-specific, genetic approach to target Erk2 using the Cre/loxP strategy with a nestin promoter-driven cre transgenic mouse line to induce recombination in the CNS. The resulting Erk2 conditional knock-out (CKO) mice, in which Erk2 was abrogated specifically in the CNS, were viable and fertile with a normal appearance. These mice, however, exhibited marked anomalies in multiple aspects of social behaviors related to facets of autism-spectrum disorders: elevated aggressive behaviors, deficits in maternal nurturing, poor nestbuilding, and lower levels of social familiarity and social interaction. Erk2 CKO mice also exhibited decreased anxiety-related behaviors and impaired long-term memory. Pharmacological inhibition of ERK1 phosphorylation in Erk2 CKO mice did not affect the impairments in social behaviors and learning disabilities, indicating that ERK2, but not ERK1 plays a critical role in these behaviors. Our findings suggest that ERK2 has complex and multiple roles in the CNS, with important implications for human psychiatric disorders characterized by deficits in social behaviors.

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Section: Generation Of Erk2 Cko Micesupporting

confidence: 93%

ERK2 Contributes to the Control of Social Behaviors in Mice

et al. 2011

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“…6,7 The subcellular distribution, stability and transcriptional potency of C/EBPb are all MAPK-dependent, 11,28 and hypoxia-dependent changes in MAPK activity can inhibit both C/EBPb nuclear translocation and DNA binding. 29 Dimerization between the more than 50 bZIP-containing factors in the human genome governs such activities as nuclear target specificity, subcellular localization and transcriptional potency.…”

Section: Resultsmentioning

confidence: 99%

“…6,7 In addition to its effects on general transcriptional potency, MEK-dependent phosphorylation of C/EBPb at Thr 188 biases cortical progenitors towards a neuronal fate in the developing CNS. 10,11 Although it is not yet known whether stress-induced MKP-1 antagonizes the pro-survival function of C/EBPb in the injured adult nervous system, we found that loss of C/EBPb expression in hypoxic neurons promotes cell death in vitro, 12 suggesting the stoichiometric relationship between the available pool of bZIP heterodimeric partners particularly important. 12,13 In the present study, we test the hypothesis that MKP-1 serves a molecular switch, exerting similar suppressive effects on the pro-survival factor C/EBPb following ischemic injury as has previously been described for HIF-1a.…”

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confidence: 75%

MKP-1 antagonizes C/EBP β activity and lowers the apoptotic threshold after ischemic injury

et al. 2012

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The dual specificity phosphatase MAPK phosphatase-1 (MKP-1) feeds back on MAP kinase signaling to regulate metabolic, inflammatory and survival responses. MKP-1 is widely expressed in the central nervous system (CNS) and induced after ischemic stress, although its function in these contexts remains unclear. Here we report that MKP-1 activated several cell death factors, including BCL2 and adenovirus E1B 19 kDa interacting protein 3, and caspases 3 and 12 culminating in apoptotic cell death in vitro. MKP-1 also exerted inhibitory effects on the bZIP transcription factor CCAAT/enhancer-binding protein (C/EBPb), previously shown to have neuroprotective properties. These effects included reduced expression of the full-length C/EBPb variant and hypo-phosphorylation at the MEK-ERK1/2-sensitive Thr 188 site. Notably, enforced expression C/EBPb rescued cells from MKP-1-induced toxicity. Studies performed in knock-out mice indicate that the MKP-1 activity is required to exclude C/EBPb from the nucleus basally, and that MKP-1 antagonizes C/EBPb expression after global forebrain ischemia, particularly within the vulnerable CA1 sector of the hippocampus. Overall, MKP-1 appears to lower the cellular apoptotic threshold by inhibiting C/EBPb and enhancing both BH3 protein expression and cellular caspase activity. Thus, although manipulation of the MKP-1-C/EBPb axis could have therapeutic value in ischemic disorders, our observations using MKP-1 catalytic mutants suggest that approaches geared towards inhibiting MKP-1's phosphatase activity alone may be ineffective.

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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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CCAAT/Enhancer-Binding Protein Phosphorylation Biases Cortical Precursors to Generate Neurons Rather Than AstrocytesIn Vivo

Cited by 76 publications

References 61 publications

ERK2 Contributes to the Control of Social Behaviors in Mice

ERK2 Contributes to the Control of Social Behaviors in Mice

MKP-1 antagonizes C/EBP β activity and lowers the apoptotic threshold after ischemic injury

Neuropathogenesis of Noonan syndrome is mediated by inflammatory microglia

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