Effect of canonical Wnt inhibition in the neurogenic cortex, hippocampus, and premigratory dentate gyrus progenitor pool

Solberg, Nina; Machoň, Ondřej; Krauß, Stefan

doi:10.1002/dvdy.21586

Cited by 42 publications

(31 citation statements)

References 51 publications

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“…Ectopic expression of Dkk1, a negative regulator of Wnt signaling pathway, in the developing cortex was used to reduce Wnt signaling activity while maintaining β-Cat function in cortical progenitors. It confirmed that Wnt signaling plays a positive role in the expansion of progenitors (39). Recently, the role of β-Cat in cortical development was studied elegantly by constructing a mutant form of β-Cat with normal cell-cell adhesion activity, but defective transcriptional activity (40).…”

Section: Discussionmentioning

confidence: 85%

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Lhx2 regulates the timing of β-catenin-dependent cortical neurogenesis

Hsu

Nam

Cui

et al. 2015

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

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The timing of cortical neurogenesis has a major effect on the size and organization of the mature cortex. The deletion of the LIMhomeodomain transcription factor Lhx2 in cortical progenitors by Nestin-cre leads to a dramatically smaller cortex. Here we report that Lhx2 regulates the cortex size by maintaining the cortical progenitor proliferation and delaying the initiation of neurogenesis. The loss of Lhx2 in cortical progenitors results in precocious radial glia differentiation and a temporal shift of cortical neurogenesis. We further investigated the underlying mechanisms at play and demonstrated that in the absence of Lhx2, the Wnt/β-catenin pathway failed to maintain progenitor proliferation. We developed and applied a mathematical model that reveals how precocious neurogenesis affected cortical surface and thickness. Thus, we concluded that Lhx2 is required for β-catenin function in maintaining cortical progenitor proliferation and controls the timing of cortical neurogenesis.cortical neurogenesis | Lhx2 | β-catenin U nderstanding how genetic mechanisms interact to set up a precise developmental timing is a fundamental issue in biology. In the cerebral cortex, excitatory neurons are generated by progenitor cells in the dorsal telencephalon (dTel) lining the lateral ventricle. During the early developmental stages, cortical progenitors undergo symmetric divisions, resulting in the proliferation of progenitors and thereby allowing expansion of the developing cortex. Soon after, cortical progenitors start generating distinct types of neurons through asymmetric differentiative divisions (1-5). The precise timing of the switch from proliferative division to differentiative division is crucial to determining the number of cortical neurons, and thus the cortical size.The switch from proliferation to differentiation is reportedly regulated by the canonical Wnt signaling pathway, in which β-catenin (β-Cat) is the major downstream effector. In the absence of Wnt signaling, β-Cat is phosphorylated by glycogen synthase kinase 3 and targeted for proteosome degradation. Once Wnt ligands bind to the Frizzled-Lrp5/6 receptors, the activity of glycogen synthase kinase 3-Axin-APC (adenomatous polyposis coli) destruction complex is inhibited. As a consequence, β-Cat accumulates in the cytoplasm, translocates to the nucleus, and activates downstream gene transcription together with the lymphoid enhancer-binding factor (LEF)/ T-cell factor (TCF) transcription factors (6). Overexpression of the stabilized, N-terminally truncated form of β-Cat in cortical progenitors during early neurogenesis promotes their overproliferation (7,8), whereas inactivation of β-Cat in the cortex promotes neurogenesis (9, 10). However, stabilized β-Cat was also shown to promote cortical progenitor differentiation (11). Thus, it has been proposed that Wnt/β-Cat signaling promotes proliferation and differentiation of cortical progenitors at early and late developmental stages, respectively (12). This raises the essential and largely open question of ho...

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Section: Discussionmentioning

confidence: 85%

“…3). Interestingly, we observed a discrepancy between the expression of the BAT-Gal reporter, a faithful reporter for Wnt/β-Cat signaling pathway in many systems (9,29,39,41,42), and the known Wnt/β-Cat downstream genes, such as Axin2 and CyclinD1 (SI Appendix, Fig. S7).…”

Section: Discussionmentioning

confidence: 99%

Lhx2 regulates the timing of β-catenin-dependent cortical neurogenesis

Hsu

Nam

Cui

et al. 2015

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

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“…Further, DKK1 inhibits neurogenesis in brain. Forced expression of DKK1 severely reduces neurogenesis in the developing mouse hippocampus [41]. DKK1 accumulates in the aging dentate gyrus, in contrast, loss of DKK1 restores neurogenesis in hippocampus and counteracts cognitive decline in old mice [42]…”

Section: Discussionmentioning

confidence: 99%

Plasma dickkopf-related protein 1, an antagonist of the Wnt pathway, is associated with HIV-associated neurocognitive impairment

Seaton²,

Letendre³

et al. 2017

Aids

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Objective DKK1 is a soluble antagonist of the Wnt pathway. It binds to and sequesters LRP5/6 away from Wnts. Because the Wnt pathway regulates synaptic transmission and plasticity, we hypothesized that increased DKK1 would increase the risk for neurocognitive impairment (NCI) in HIV+ individuals. We evaluated here the relationship between plasma DKK1 and global NCI. Methods Plasma samples and data from 41 HIV+ and 42 HIV− adults were obtained from the University of California, San Diego. Concentrations of DKK1 and a comparator protein, MCP-1, were quantified in plasma by immunoassay. All subjects completed a standardized comprehensive neuropsychological test battery and their performance was summarized using the global deficit score (GDS) method. Results A higher DKK1 level was associated with NCI among HIV+ participants (d=0.63, p=0.05), particularly among the 26 participants whose plasma HIV RNA level was suppressed (d=0.74, p=0.08). DKK1 level was not associated with NCI among HIV− participants (p=0.98). MCP-1 was not associated with NCI in either group. In HIV+ adults with suppressed plasma HIV RNA, a receiver-operator characteristic curve identified that a DKK1 level of at least 735 pg/ml had a positive predictive value of 83.3% for a diagnosis of NCI. This association did not weaken after accounting for the effect of AIDS, nadir CD4+ T-cell count, addictive drug use, or demographic characteristics. Conclusion DKK1 is a specific biomarker for NCI in HIV+ adults, implicating the Wnt pathway in HIV neuropathogenesis.

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“…The nuclear localization of ␤-catenin in mature neurons is unusual. In the adult brain, nuclear ␤-catenin is generally restricted to neural progenitor cells as a mediator of the Wnt signaling pathway (37,38). Thus, the nuclear pattern of ␤-catenin in postmitotic neurons of the adult thalamus would suggest persistent Wnt pathway activity in this brain region.…”

Section: Discussionmentioning

confidence: 99%

WNT Protein-independent Constitutive Nuclear Localization of β-Catenin Protein and Its Low Degradation Rate in Thalamic Neurons

Misztal

Wisniewska

Ambrozkiewicz

et al. 2011

Journal of Biological Chemistry

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Nuclear localization of ␤-catenin is a hallmark of canonical Wnt signaling, a pathway that plays a crucial role in brain development and the neurogenesis of the adult brain. We recently showed that ␤-catenin accumulates specifically in mature thalamic neurons, where it regulates the expression of the Ca v 3.1 voltage-gated calcium channel gene. Here, we investigated the mechanisms underlying ␤-catenin accumulation in thalamic neurons. We report that a lack of soluble factors produced either by glia or cortical neurons does not impair nuclear ␤-catenin accumulation in thalamic neurons. We next found that the number of thalamic neurons with ␤-catenin nuclear localization did not change when the Wnt/Dishevelled signaling pathway was inhibited by Dickkopf1 or a dominant negative mutant of Dishevelled3. These results suggest a WNT-independent cellautonomous mechanism. We found that the protein levels of APC, AXIN1, and GSK3␤, components of the ␤-catenin degradation complex, were lower in the thalamus than in the cortex of the adult rat brain. Reduced levels of these proteins were also observed in cultured thalamic neurons compared with cortical cultures. Finally, pulse-chase experiments confirmed that cytoplasmic ␤-catenin turnover was slower in thalamic neurons than in cortical neurons. Altogether, our data indicate that the nuclear localization of ␤-catenin in thalamic neurons is their cell-intrinsic feature, which was WNT-independent but associated with low levels of proteins involved in ␤-catenin labeling for ubiquitination and subsequent degradation.

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Effect of canonical Wnt inhibition in the neurogenic cortex, hippocampus, and premigratory dentate gyrus progenitor pool

Cited by 42 publications

References 51 publications

Lhx2 regulates the timing of β-catenin-dependent cortical neurogenesis

Lhx2 regulates the timing of β-catenin-dependent cortical neurogenesis

Plasma dickkopf-related protein 1, an antagonist of the Wnt pathway, is associated with HIV-associated neurocognitive impairment

WNT Protein-independent Constitutive Nuclear Localization of β-Catenin Protein and Its Low Degradation Rate in Thalamic Neurons

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