In Vivo Fate Analysis Reveals the Multipotent and Self-Renewal Capacities of Sox2+ Neural Stem Cells in the Adult Hippocampus

Suh, Hoonkyo; Consiglio, Antonella; Ray, Jasodhara; Sawai, Toru; D’Amour, Kevin A.; Gage, Fred H.

doi:10.1016/j.stem.2007.09.002

Cited by 733 publications

(756 citation statements)

References 41 publications

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“…16 Of note, Sox2 is highly expressed in the neurogenetic tissues, such as the hippocampus and central canal, and has a critical role in unperturbed neurogenesis. [17][18][19] These insights corroborate our interest in exploring the role of K11-linked polyubiquitin chain assembly machineries in fine-tuning the precise level of Sox2 in mES cells.…”

supporting

confidence: 60%

“…Interestingly, the importance of the interaction extends to the role of Ube2s in regulating ES cell differentiation to the neural ectoderm lineage. As Sox2 is important for neurogenesis in the adult central nerve system through its maintenance of neural stem and progenitor cells, [17][18][19] as a regulator of Sox2 ubiquitination, Ube2s may have yet unexplored role in regulating neurogenesis, and its dysfunction may be related to neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 99%

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Ube2s regulates Sox2 stability and mouse ES cell maintenance

et al. 2015

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Sox2 has a critical role in embryonic stem (ES) cell maintenance and differentiation. Interestingly, its activity is highly dosagedependent. Although transcriptional regulation of Sox2 has been extensively studied, the mechanisms orchestrating its degradation remain unclear. In this study, we identified ubiquitin-conjugating enzyme E2S (Ube2s) as a novel effector for Sox2 protein degradation. Ube2s mediates K11-linked polyubiquitin chain formation at the Sox2-K123 residue, thus marking it for proteasome-mediated degradation. Besides its role in fine-tuning the precise level of Sox2, Ube2s reinforces the self-renewing and pluripotent state of ES cells. Importantly, it also represses Sox2-mediated ES cell differentiation toward the neural ectodermal lineage.

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supporting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Ube2s regulates Sox2 stability and mouse ES cell maintenance

et al. 2015

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“…Generation of neurons from neural progenitors in the adult DG has been proposed to take 2-4 weeks, but timing has been hampered by the experimental approaches used 6,14,19,29 . We analyzed the Hes5CreER T2 mice seven days (d7) and 3 weeks after TAM induction (d21; Fig.…”

Section: Hes5creermentioning

confidence: 99%

Homeostatic neurogenesis in the adult hippocampus does not involve amplification of Ascl1high intermediate progenitors

et al. 2012

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neural stem/progenitor cells generate neurons in the adult hippocampus. neural stem cells produce transient intermediate progenitors (type-2 cells), which generate neuroblasts (type-3 cells) that exit the cell cycle, and differentiate into neurons. The precise dynamics of neuron production from the neural stem cells remains controversial. Here we lineage trace notchdependent neural stem cells in the dentate gyrus and show that over 7-21 days, the progeny of the neural stem cells progress through an Ascl1 high intermediate stage (type-2a) to neuroblasts. However, contrary to predictions, this Ascl1 high population is not an amplifying intermediate, but it differentiates into mitotic Tbr2 + early neuroblasts, which in turn expand the lineage. After 100 days, the majority of the neural stem cell progeny are neuroblasts or postmitotic neurons. Hence, the neural stem cells require many weeks to generate differentiated neurons. on the basis of this temporal delay in differentiation and population expansion, we propose that the neural stem cell and early neuroblast divisions drive dentate gyrus neurogenesis and not the amplification of type-2a intermediate progenitors as was previously thought.

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“…Previous works have demonstrated that cell cycle regulation in the adult brain is precursor-type-specific [24], thus we sought to determine whether the defect in proliferation observed in Cdk6 À/À brains was restricted to a subpopulation versus all cycling precursors. First, we used glial fibrillary acidic protein (GFAP) and the Sry-related HMG box transcription factor Sox2 to identify immature DG precursors with, respectively, radial (type 1) and nonradial (type 2a) morphology that are not yet restricted to a neuronal fate [25]. No significant differences in the number of proliferating GFAP þ (i.e., GFAP þ /Ki-67 þ ) nor Sox2 þ (i.e., Sox2 þ /Ki-67 þ ) precursors were found in Cdk6 À/À mice ( Fig.…”

Section: Cdk6 Selectively Regulates the Proliferation Of Neuronally Cmentioning

confidence: 99%

Cdk6-Dependent Regulation of G1 Length Controls Adult Neurogenesis

et al. 2011

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The presence of neurogenic precursors in the adult mammalian brain is now widely accepted, but the mechanisms coupling their proliferation with the onset of neuronal differentiation remain unknown. Here, we unravel the major contribution of the G 1 regulator cyclin-dependent kinase 6 (Cdk6) to adult neurogenesis. We found that Cdk6 was essential for cell proliferation within the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricles. Specifically, Cdk6 deficiency prevents the expansion of neuronally committed precursors by lengthening G 1 phase duration, reducing concomitantly the production of newborn neurons. Altogether, our data support G 1 length as an essential regulator of the switch between proliferation and neuronal differentiation in the adult brain and Cdk6 as one intrinsic key molecular regulator of this process. STEM CELLS 2011;29:713-724 Disclosure of potential conflicts of interest is found at the end of this article.

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In Vivo Fate Analysis Reveals the Multipotent and Self-Renewal Capacities of Sox2+ Neural Stem Cells in the Adult Hippocampus

Cited by 733 publications

References 41 publications

Ube2s regulates Sox2 stability and mouse ES cell maintenance

Ube2s regulates Sox2 stability and mouse ES cell maintenance

Homeostatic neurogenesis in the adult hippocampus does not involve amplification of Ascl1high intermediate progenitors

Cdk6-Dependent Regulation of G1 Length Controls Adult Neurogenesis

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