The Role of GSK3β in Regulating Neuronal Differentiation inXenopus laevis

Marcus, Emilie A.; Kintner, Chris; Harris, William A.

doi:10.1006/mcne.1998.0713

Cited by 49 publications

(29 citation statements)

References 40 publications

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“…This led us to hypothesize that GSK3 may be a negative regulator of Neurog2 proneural activity at later developmental stages. Consistent with this idea, GSK3 negatively regulates X-Neurod1 in Xenopus and NeuroAB in chick (Marcus et al, 1998;Moore et al, 2002;Ohkawara et al, 2004).…”

Section: Temporal Regulation Of Neurog2 Activity By Gsk3 Phosphorylationsupporting

confidence: 59%

“…Given that many bHLH transcription factors, including Neurog2, are directly and/or indirectly regulated by phosphorylation (Marcus et al, 1998;Moore et al, 2002;Hand et al, 2005;Ma et al, 2008), we focused on GSK3, which is sequestered to membrane-bound multivesicular bodies during canonical Wnt signaling, reducing its activity in the cytoplasm and nucleus (Hur and Zhou, 2010;Taelman et al, 2010). Consequently, we predicted that GSK3 activity would be low in early corticogenesis when canonical Wnt signaling was elevated, and vice versa at later stages.…”

Section: Gsk3␤ Activity Levels and Neurog2 Phosphorylation Increase Omentioning

confidence: 99%

“…We speculated that temporally regulated posttranslational modifications may modify Neurog2 proneural activity at different developmental times. We focused on phosphorylation, which regulates the activities of several bHLH proteins, including Neurog2 (Marcus et al, 1998;Moore et al, 2002;Ohkawara et al, 2004;Hand et al, 2005;Ge et al, 2006;Ma et al, 2008;Ali et al, 2011). Here, we show that the ability of Neurog2 to induce rapid neurogenesis is dramatically reduced in mid-corticogenesis.…”

Section: Introductionmentioning

confidence: 99%

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GSK3 Temporally Regulates Neurogenin 2 Proneural Activity in the Neocortex

Li¹,

Mattar²,

Zinyk³

et al. 2012

Journal of Neuroscience

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The neocortex is comprised of six neuronal layers that are generated in a defined temporal sequence. While extrinsic and intrinsic cues are known to regulate the sequential production of neocortical neurons, how these factors interact and function in a coordinated manner is poorly understood. The proneural gene Neurog2 is expressed in progenitors throughout corticogenesis, but is only required to specify early-born, deep-layer neuronal identities. Here, we examined how neuronal differentiation in general and Neurog2 function in particular are temporally controlled during murine neocortical development. We found that Neurog2 proneural activity declines in late corticogenesis, correlating with its phosphorylation by GSK3 kinase. Accordingly, GSK3 activity, which is negatively regulated by canonical Wnt signaling, increases over developmental time, while Wnt signaling correspondingly decreases. When ectopically activated, GSK3 inhibits Neurog2-mediated transcription in cultured cells and Neurog2 proneural activities in vivo. Conversely, a reduction in GSK3 activity promotes the precocious differentiation of later stage cortical progenitors without influencing laminar fate specification. Mechanistically, we show that GSK3 suppresses Neurog2 activity by influencing its choice of dimerization partner, promoting heterodimeric interactions with E47 (Tcfe2a), as opposed to Neurog2-Neurog2 homodimer formation, which occurs when GSK3 activity levels are low. At the functional level, Neurog2-E47 heterodimers have a reduced ability to transactivate neuronal differentiation genes compared with Neurog2-Neurog2 homodimers, both in vitro and in vivo. We thus conclude that the temporal regulation of Neurog2-E47 heterodimerization by GSK3 is a central component of the neuronal differentiation "clock" that coordinates the timing and tempo of neocortical neurogenesis in mouse.

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Section: Temporal Regulation Of Neurog2 Activity By Gsk3 Phosphorylationsupporting

confidence: 59%

Section: Gsk3␤ Activity Levels and Neurog2 Phosphorylation Increase Omentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

GSK3 Temporally Regulates Neurogenin 2 Proneural Activity in the Neocortex

Li¹,

Mattar²,

Zinyk³

et al. 2012

Journal of Neuroscience

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show abstract

“…Interestingly, however, inhibition of GSK3β activity has been also associated with an increase of neuron differentiation in both Drosophila (Bourouis et al, 1989) and Xenopus embryos (Marcus et al, 1998;Moore et al, 2002). Therefore, we have asked whether SFRP1 activity could involve inhibition of GSK3β, hypothesising that Sfrp1 mechanism of action might be different from that of an extracellular Wnt antagonist.…”

Section: Sfrp1 Induces Differentiation Of Retinal Neuroepithelial Cellsmentioning

confidence: 99%

SFRP1 modulates retina cell differentiation through aβ-catenin-independent mechanism

Esteve

Trousse

Rodríguez

et al. 2003

Journal of Cell Science

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Secreted frizzled related proteins (SFRPs) are soluble molecules capable of binding WNTS and preventing the activation of their canonical signalling cascade. Here we show that Sfrp1 contributes to chick retina differentiation with a mechanism that does not involve modifications in the transcriptional activity of β-catenin. Thus, addition of SFRP1 to dissociated retinal cultures or retroviral mediated overexpression of the molecule consistently promoted retinal ganglion and cone photoreceptor cell generation, while decreasing the number of amacrine cells. Measure of the activity of the β-catenin-responsive Tcf-binding site coupled to a luciferase reporter in transiently transfected retinal cells showed that Sfrp1 was unable to modify the basal β-catenin transcriptional activity of the retina cells. Interestingly, a dominant-negative form of GSK3β gave similar results to those of Sfrp1, and a phosphorylation-dependent inhibition of GSK3β activity followed SFRP1 treatment of retina cells. Furthermore, retroviral mediated expression of a dominant-negative form of GSK3β induced a retina phenotype similar to that observed after Sfrp1 overexpression, suggesting a possible involvement of this kinase in SFRP1 function.

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“…Akt phosphorylates GSK3␣ and GSK3␤ and negatively regulates their enzymatic activity (71). Marcus et al reported that GSK3␤ inhibits the function of XNeuroD1 and prevents neurogenesis in Xenopus (43). Vetter and colleagues demonstrated that the integrity of a GSK3 consensus phosphorylation site in Xenopus and mouse neuroD is critical for proper regulation of the timing of NeuroD function (48).…”

mentioning

confidence: 99%

Akt Regulates Basic Helix-Loop-Helix Transcription Factor–Coactivator Complex Formation and Activity during Neuronal Differentiation

Vojtek¹,

Taylor²,

DeRuiter

et al. 2003

Molecular and Cellular Biology

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Neural basic helix-loop-helix (bHLH) transcription factors regulate neurogenesis in vertebrates.Signaling by peptide growth factors also plays critical roles in regulating neuronal differentiation and survival. Many peptide growth factors activate phosphatidylinositol 3-kinase (PI3K) and subsequently the Akt kinases, raising the possibility that Akt may impact bHLH protein function during neurogenesis. Here we demonstrate that reducing expression of endogenous Akt1 and Akt2 by RNA interference (RNAi) reduces neuron generation in P19 cells transfected with a neural bHLH expression vector. The reduction in neuron generation from decreased Akt expression is not solely due to decreased cell survival, since addition of the caspase inhibitor z-VAD-FMK rescues cell death associated with loss of Akt function but does not restore neuron formation. This result indicates that Akt1 and Akt2 have additional functions during neuronal differentiation that are separable from neuronal survival. We show that activated Akt1 enhances complex formation between bHLH proteins and the transcriptional coactivator p300. Activated Akt1 also significantly augments the transcriptional activity of the bHLH protein neurogenin 3 in complex with the coactivators p300 or CBP. In addition, inhibition of endogenous Akt activity by the PI3K/Akt inhibitor LY294002 abolishes transcriptional cooperativity between the bHLH proteins and p300. We propose that Akt regulates the assembly and activity of bHLH-coactivator complexes to promote neuronal differentiation.

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The Role of GSK3β in Regulating Neuronal Differentiation inXenopus laevis

Cited by 49 publications

References 40 publications

GSK3 Temporally Regulates Neurogenin 2 Proneural Activity in the Neocortex

GSK3 Temporally Regulates Neurogenin 2 Proneural Activity in the Neocortex

SFRP1 modulates retina cell differentiation through aβ-catenin-independent mechanism

Akt Regulates Basic Helix-Loop-Helix Transcription Factor–Coactivator Complex Formation and Activity during Neuronal Differentiation

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