Return to quiescence of mouse neural stem cells by degradation of a                    proactivation protein

Urbán, Noelia; Berg, Debbie L. C. van den; Forget, Antoine; Andersen, Jimena; Demmers, Jeroen; Hunt, Charles J.; Ayrault, Olivier; Guillemot, François

doi:10.1126/science.aaf4802

Cited by 222 publications

(222 citation statements)

References 35 publications

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“…For these reasons, the role of Mule in various tissues, whether at steady state or in disease, had been elusive. During the last year, we and others have exploited different Mule knockout mouse models to demonstrate that Mule is involved in the regulation of intestinal, hematopoietic, and neural stem cells (8,15,16). Significantly, the developmental programs of all these tissues are driven by the Wnt pathway (17)(18)(19).…”

Section: Discussionmentioning

confidence: 99%

E3 ubiquitin ligase Mule targets β-catenin under conditions of hyperactive Wnt signaling

Dominguez-Brauer

Khatun

Elia

et al. 2017

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

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Wnt signaling, named after the secreted proteins that bind to cell surface receptors to activate the pathway, plays critical roles both in embryonic development and the maintenance of homeostasis in many adult tissues. Two particularly important cellular programs orchestrated by Wnt signaling are proliferation and stem cell selfrenewal. Constitutive activation of the Wnt pathway resulting from mutation or improper modulation of pathway components contributes to cancer development in various tissues. Colon cancers frequently bear inactivating mutations of the adenomatous polyposis coli (APC) gene, whose product is an important component of the destruction complex that regulates β-catenin levels. Stabilization and nuclear localization of β-catenin result in the expression of a panel of Wnt target genes. We previously showed that Mule/ Huwe1/Arf-BP1 (Mule) controls murine intestinal stem and progenitor cell proliferation by modulating the Wnt pathway via c-Myc. Here we extend our investigation of Mule's influence on oncogenesis by showing that Mule interacts directly with β-catenin and targets it for degradation under conditions of hyperactive Wnt signaling. Our findings suggest that Mule uses various mechanisms to finetune the Wnt pathway and provides multiple safeguards against tumorigenesis.β-catenin | Mule | Wnt signaling | stem cells | colorectal cancer A ctivation of the Wnt pathway, named after the secreted proteins that bind to cell surface receptors to activate the pathway, plays a critical role in stem cell self-renewal, and thus the homeostasis of normal mammalian tissues. However, constitutive activation of Wnt signaling has been implicated in a broad range of cancers, including melanoma, hepatocellular carcinoma, and cancers of the prostate, thyroid, ovary, and breast (1-3). Perhaps the best-studied malignancy arising from the loss of regulation of the Wnt signaling pathway is colorectal cancer, which develops through a multistage process driven by the progressive accumulation of genetic mutations (4). The key initial activating mutation occurs in components of the Wnt pathway, but most commonly in APC.Canonical Wnt signaling involves a relay of protein interactions that serve to transmit a signal from the extracellular space to the plasma membrane. This signal is amplified in the cytoplasm and then directed to the nucleus to culminate in the activation of the Wnt target gene program. In molecular terms, when the glycoprotein Wnt is secreted into the extracellular space, it binds to a cell's Frizzled receptors in conjunction with the low-density lipoprotein receptorrelated proteins 5 and 6 (LRP5/6). The engagement of these receptors recruits the scaffolding protein Dishevelled (Dvl), leading to LRP5/6 phosphorylation and consequent recruitment of the scaffolding protein, Axin2 and glycogen synthase kinase 3 beta (GSK-3β). This recruitment results in disruption of the "destruction complex" that contains APC and normally binds to the signal transduction protein β-catenin to trigger its degradation. On Wn...

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Section: Discussionmentioning

confidence: 99%

E3 ubiquitin ligase Mule targets β-catenin under conditions of hyperactive Wnt signaling

Dominguez-Brauer

Khatun

Elia

et al. 2017

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

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“…In the absence of Huwe1, Ascl1 protein persisted in later stages of the lineage, into the basal or intermediate progenitors, which then continue to amplify the neuronal lineage for longer. Intriguingly, a different phenotype was observed in the context of adult neurogenesis, whereby increased persistence of Ascl1 interfered with return to quiescence, thus depleting the pool of adult neural stem cells (NSCs) (Urban et al, 2016). Given that different levels of Ascl1 play a key role in regulating aspects of cell cycle entry and progression, it is surprising that this function has not been observed in reprogramming experiments that use Ascl1 (Wapinski et al, 2013;Masserdotti et al, 2015).…”

Section: Programming the Brainmentioning

confidence: 98%

“…François Guillemot (The Francis Crick Institute, London, UK) examined how the pool of adult NSCs is maintained over time in the postnatal dentate gyrus (Urban et al, 2016). The transcription factor Ascl1 was found to play a key role both in the activation of quiescent stem cells into dividing stem cells, as well as in the return to quiescence of the progeny of activated stem cells.…”

Section: Programming Adult Nscsmentioning

confidence: 99%

Programming and reprogramming the brain: a meeting of minds in neural fate

Götz

Jarriault

2017

Development

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In early April 2017, over 130 delegates met in Munich, Germany, to discuss the latest research in the development and reprogramming of cells of the nervous system. The conference, which was organised by Abcam and entitled 'Programming and Reprogramming the Brain', was a great success, and provided an excellent snapshot of the current state of the field, and what the challenges are for the future. This Meeting Review provides a summary of the talks presented and the major themes that emerged from the conference.

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“…The basic helix-loop-helix protein ASCL1 is a proneural factor required for AH-NSCs to enter the cell-cycle (Andersen et al, 2014;Urban et al, 2016). Because ASCL1 protein is not expressed by quiescent AH-NSCs and labels only a fraction of IPs , it displays good specificity.…”

Section: Selecting a Nuclear Marker For Dividing Ah-nscsmentioning

confidence: 99%

The function of NFIX during developmental and adult neurogenesis

Harris¹

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Understanding the transcription factor proteins that control the biology of neural stem cells during embryogenesis provides insight into brain development as well as neurodevelopmental disorders.Likewise, studying the function of transcription factors in adult neural stem cells allows us to appreciate the dynamics of these cells and their contribution to normal cognitive function. It also provides a knowledge base so as to one day harness the activity of adult neural stem cells to treat degenerative conditions of the nervous system.One family of transcription factors key to brain development are the Nuclear Factor Ones (NFIs).Comprised of four members in mammals (NFIA, NFIB, NFIC and NFIX) these proteins promote both neuronal and glial differentiation during mouse forebrain development, and in general, appear to have a highly similar function. This thesis addressed two outstanding questions regarding the function of one these proteins, NFIX, in mouse neural stem cell biology. The first question concerned refining our understanding of NFIX function during forebrain development by determining, which stage of neuron differentiation, from a stem cell to a mature neuron, is The second question I addressed in this thesis, was that if NFI proteins are so important for regulating neural stem cell biology during brain development, then do they also regulate adult neural stem cell biology? I addressed this question by breeding inducible, conditional mice to allow for deletion of Nfix from adult hippocampal neural stem cells and separately, immature neurons. I found that NFIX is essential for adult-borne neuron differentiation, so that in the absence of NFIX, mature neurons are not generated and behavioural deficits ensue. Mechanistically, we found that NFIX is essential for primary dendrite formation, and that without NFIX a proportion of adult hippocampal progenitors switch fate to become oligodendrocytes or aberrantly express increased levels of oligodendrocyte mRNA. In addition to demonstrating the absolute requirement of the NFIX protein for the generation of adult-borne neurons, these findings reveal the surprising tri-

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Return to quiescence of mouse neural stem cells by degradation of a proactivation protein

Cited by 222 publications

References 35 publications

E3 ubiquitin ligase Mule targets β-catenin under conditions of hyperactive Wnt signaling

E3 ubiquitin ligase Mule targets β-catenin under conditions of hyperactive Wnt signaling

Programming and reprogramming the brain: a meeting of minds in neural fate

The function of NFIX during developmental and adult neurogenesis

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