Interaction and Antagonistic Roles of NF-κB and Hes6 in the Regulation of Cortical Neurogenesis

Methot, Laurent; Hermann, Robert Michael; Tang, Yeman; Lo, Rita; Al-Jehani, Hosam; Jhas, Sumit; Svoboda, Devon S.; Slack, Ruth S.; Barker, Philip A.; Stifani, Stefano

doi:10.1128/mcb.01610-12

Cited by 24 publications

(34 citation statements)

References 52 publications

(79 reference statements)

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“…They also regulate embryonic brain development; interfering with NF-κB signaling results in premature differentiation of cortical progenitors, and subsequent depletion of the progenitor pool [23]. However, it seems unlikely that disruption of NF-κB signaling could be entirely responsible for the observed phenotype of Akirin2 knockouts: While we see massive loss of dorsal telencephalic tissue between E10 and E12, an NF-κB activity reporter mouse [23] exhibits a pattern that begins ventrolaterally at E11 and even at E13.5 remains patchy dorsally. However, it remains entirely possible that NF-κB interacts with Akirin2 in postmitotic neurons, which also express the Akirin2 gene (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Progenitor proliferation requires the presence of the BAF53A subunit in the BAF complex; a switch from BAF53A to BAF53B is critical for the generation and differentiation of neurons and the elaboration of dendritic arbors by forebrain neurons [22]. Both NF-κB [23] and 14-3-3 proteins [24] have also been reported to regulate the onset and progression of neuronal differentiation in the cortex. Therefore, as a protein that interacts with NF-κB proteins, 14-3-3 proteins, and the BAF chromatin remodeling complex, Akirin2 is well-placed to have an important, previously-undocumented role in cortical development.…”

Section: Introductionmentioning

confidence: 99%

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Akirin2 is essential for the formation of the cerebral cortex

et al. 2016

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BackgroundThe proper spatial and temporal regulation of dorsal telencephalic progenitor behavior is a prerequisite for the formation of the highly-organized, six-layered cerebral cortex. Premature differentiation of cells, disruption of cell cycle timing, excessive apoptosis, and/or incorrect neuronal migration signals can have devastating effects, resulting in a number of neurodevelopmental disorders involving microcephaly and/or lissencephaly. Though genes encoding many key players in cortical development have been identified, our understanding remains incomplete. We show that the gene encoding Akirin2, a small nuclear protein, is expressed in the embryonic telencephalon. Converging evidence indicates that Akirin2 acts as a bridge between transcription factors (including Twist and NF-κB proteins) and the BAF (SWI/SNF) chromatin remodeling machinery to regulate patterns of gene expression. Constitutive knockout of Akirin2 is early embryonic lethal in mice, while restricted loss in B cells led to disrupted proliferation and cell survival.MethodsWe generated cortex-restricted Akirin2 knockouts by crossing mice harboring a floxed Akirin2 allele with the Emx1-Cre transgenic line and assessed the resulting embryos using in situ hybridization, EdU labeling, and immunohistochemistry.ResultsThe vast majority of Akirin2 mutants do not survive past birth, and exhibit extreme microcephaly, with little dorsal telencephalic tissue and no recognizable cortex. This is primarily due to massive cell death of early cortical progenitors, which begins at embryonic day (E)10, shortly after Emx1-Cre is active. Immunostaining and cell cycle analysis using EdU labeling indicate that Akirin2-null progenitors fail to proliferate normally, produce fewer neurons, and undergo extensive apoptosis. All of the neurons that are generated in Akirin2 mutants also undergo apoptosis by E12. In situ hybridization for Wnt3a and Wnt-responsive genes suggest defective formation and/or function of the cortical hem in Akirin2 null mice. Furthermore, the apical ventricular surface becomes disrupted, and Sox2-positive progenitors are found to “spill” into the lateral ventricle.ConclusionsOur data demonstrate a previously-unsuspected role for Akirin2 in early cortical development and, given its known nuclear roles, suggest that it may act to regulate gene expression patterns critical for early progenitor cell behavior and cortical neuron production.Electronic supplementary materialThe online version of this article (doi:10.1186/s13064-016-0076-8) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Akirin2 is essential for the formation of the cerebral cortex

et al. 2016

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“…11,12,15,37 Three days following transfection, cells were analyzed by immunofluorescence using antibodies against Ki67 (1 : 500; BD Pharmingen), nestin (1 : 100; Millipore), Sox2 (1 : 250; R&D Systems), type III b-tubulin (1 : 1000; Promega, Madison, WI, USA), MAP2 (1 : 1000; Sigma-Aldrich) and NeuN (1 : 250; Millipore), as described. 41,43 Cells were counterstained with Hoechst 33258 (Sigma-Aldrich) before examination by fluorescence microscopy. Grayscale images were digitally assigned to the appropriate red or green channel using Northern Eclipse software (Empix Imaging, Inc., Mississauga, ON, Canada).…”

Section: Discussionmentioning

confidence: 99%

Prolyl isomerase Pin1 and protein kinase HIPK2 cooperate to promote cortical neurogenesis by suppressing Groucho/TLE:Hes1-mediated inhibition of neuronal differentiation

et al. 2013

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The Groucho/transducin-like Enhancer of split 1 (Gro/TLE1):Hes1 transcriptional repression complex acts in cerebral cortical neural progenitor cells to inhibit neuronal differentiation. The molecular mechanisms that regulate the anti-neurogenic function of the Gro/TLE1:Hes1 complex during cortical neurogenesis remain to be defined. Here we show that prolyl isomerase Pin1 (peptidyl-prolyl cis-trans isomerase NIMA-interacting 1) and homeodomain-interacting protein kinase 2 (HIPK2) are expressed in cortical neural progenitor cells and form a complex that interacts with the Gro/TLE1:Hes1 complex. This association depends on the enzymatic activities of both HIPK2 and Pin1, as well as on the association of Gro/TLE1 with Hes1, but is independent of the previously described Hes1-activated phosphorylation of Gro/TLE1. Interaction with the Pin1:HIPK2 complex results in Gro/TLE1 hyperphosphorylation and weakens both the transcriptional repression activity and the anti-neurogenic function of the Gro/ TLE1:Hes1 complex. These results provide evidence that HIPK2 and Pin1 work together to promote cortical neurogenesis, at least in part, by suppressing Gro/TLE1:Hes1-mediated inhibition of neuronal differentiation. Cell Death and Differentiation (2014) 21, 321-332; doi:10.1038/cdd.2013.160; published online 22 November 2013During mammalian brain development, the ventricular zone of the dorsolateral region of the alar telencephalon (neocortex) contains undifferentiated neural progenitor cells that initially undergo symmetric (proliferative) divisions to generate two new progenitor cells and later undergo asymmetric (differentiative) divisions to give rise to a new mitotic progenitor and a post-mitotic neuron.

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“…In addition, both HES6 and nuclear factor-jB mutually inhibit one another, and their balance prevents premature neuronal differentiation and maintains progenitor pool during periods of brain development (Methot et al 2013). However, overexpression of Hes6 induced neuronal apoptosis in a p53-dependent manner (Eun et al 2010).…”

Section: Discussionmentioning

confidence: 98%

Hairy and Enhancer of Split 6 (Hes6) Deficiency in Mouse Impairs Neuroblast Differentiation in Dentate Gyrus Without Affecting Cell Proliferation and Integration into Mature Neurons

Nam

Kim

et al. 2015

Cell Mol Neurobiol

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Hes6 is a member of the hairy-enhancer of split homolog (Hes) family of transcription factors and interacts with other Hes family genes. During development, Hes genes are expressed in neural stem cells and progenitor cells. However, the role of Hes6 in adult hippocampal neurogenesis remains unclear. We therefore investigated the effects of Hes6 on adult hippocampal neurogenesis, by comparing Hes6 knockout and wild-type mice. To this end, we immunostained for markers of neural stem cells and progenitor cells (nestin), proliferating cells (Ki67), post-mitotic neuroblasts and immature neurons (doublecortin, DCX), mature neuronal cells (NeuN), and astrocyte (S100β). We also injected 5-bromo-2'-deoxyuridine (BrdU) to trace the fate of mitotic cells. Nestin- and Ki67-positive proliferating cells did now show any significant differences between wild and knockout groups. Hes6 knockout negatively affects neuroblast differentiation based on DCX immunohistochemistry. On the contrary, the ratio of the BrdU and NeuN double-positive cells did not show any significance, even though it was slightly higher in the knockout group. These results suggest that Hes6 is involved in the regulation of neuroblast differentiation during adult neurogenesis, but does not influence integration into mature neurons.

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Interaction and Antagonistic Roles of NF-κB and Hes6 in the Regulation of Cortical Neurogenesis

Cited by 24 publications

References 52 publications

Akirin2 is essential for the formation of the cerebral cortex

Akirin2 is essential for the formation of the cerebral cortex

Prolyl isomerase Pin1 and protein kinase HIPK2 cooperate to promote cortical neurogenesis by suppressing Groucho/TLE:Hes1-mediated inhibition of neuronal differentiation

Hairy and Enhancer of Split 6 (Hes6) Deficiency in Mouse Impairs Neuroblast Differentiation in Dentate Gyrus Without Affecting Cell Proliferation and Integration into Mature Neurons

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