Notch2 signaling regulates Id4 and cell cycle genes to maintain neural stem cell quiescence in the adult hippocampus

Zhang, Runrui; Boareto, Marcelo; Engler, Andrea; Louvi, Angeliki; Giachino, Claudio; Iber, Dagmar; Taylor, Verdon

doi:10.1101/420620

Cited by 4 publications

(12 citation statements)

References 54 publications

(77 reference statements)

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“…In this line, in adult hippocampal NSCs it has been reported that, in order to return to the quiescent state, the pro-activation transcription factor ASCL1 is destabilized by the E3-ubiquitin ligase Huwe1 (Urbán et al, 2016). The degradation of ASCL1 is further promoted by Id4 expressed in quiescent radial glia-like NSCs (Blomfield et al, 2019;Zhang et al, 2019), while in muscle stem cells MyoD is transcribed during quiescence yet its translation is inhibited by an RNA-binding protein (de Morrée et al, 2017). A common emerging theme, therefore, is that transcription factors involved in shaping the transcriptional landscape of active and quiescent adult stem cells require fine post-transcriptional regulation to fulfill their function.…”

Section: Discussionmentioning

confidence: 98%

“…The same comparison with genes that were putatively regulated by A-specific or PAN enhancers was not significant (p > 0.05, Chi-squared test). Among these 406 upregulated genes, we encountered genes expressed by hippocampal dentate gyrus precursors throughout embryonic and postnatal development (Hopx) (Berg et al, 2019), as well as genes enriched in quiescent adult radial-glia like NSCs (Id4) (Blomfield et al, 2019;Zhang et al, 2019). Out of the 406 genes, 126 showed the LEF1 motif exclusively in the Q enhancers (this is, they lacked the motif in the PAN and A enhancers, Supplementary Table S3; note that 115 out of the 126 genes had both LEF1 and NFIX motifs at one or more Q-specific enhancers).…”

Section: Lef1 Binding Motifs Enriched In Nspc Enhancers and Putative ...mentioning

confidence: 99%

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The transcription factor LEF1 interacts with NFIX and switches isoforms during adult hippocampal neural stem cell quiescence

García-Corzo

Calatayud-Baselga

Casares-Crespo

et al. 2022

Front. Cell Dev. Biol.

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Stem cells in adult mammalian tissues are held in a reversible resting state, known as quiescence, for prolonged periods of time. Recent studies have greatly increased our understanding of the epigenetic and transcriptional landscapes that underlie stem cell quiescence. However, the transcription factor code that actively maintains the quiescence program remains poorly defined. Similarly, alternative splicing events affecting transcription factors in stem cell quiescence have been overlooked. Here we show that the transcription factor T-cell factor/lymphoid enhancer factor LEF1, a central player in canonical β-catenin-dependent Wnt signalling, undergoes alternative splicing and switches isoforms in quiescent neural stem cells. We found that active β-catenin and its partner LEF1 accumulated in quiescent hippocampal neural stem and progenitor cell (Q-NSPC) cultures. Accordingly, Q-NSPCs showed enhanced TCF/LEF1-driven transcription and a basal Wnt activity that conferred a functional advantage to the cultured cells in a Wnt-dependent assay. At a mechanistic level, we found a fine regulation of Lef1 gene expression. The coordinate upregulation of Lef1 transcription and retention of alternative spliced exon 6 (E6) led to the accumulation of a full-length protein isoform (LEF1-FL) that displayed increased stability in the quiescent state. Prospectively isolated GLAST + cells from the postnatal hippocampus also underwent E6 retention at the time quiescence is established in vivo. Interestingly, LEF1 motif was enriched in quiescence-associated enhancers of genes upregulated in Q-NSPCs and quiescence-related NFIX transcription factor motifs flanked the LEF1 binding sites. We further show that LEF1 interacts with NFIX and identify putative LEF1/NFIX targets. Together, our results uncover an unexpected role for LEF1 in gene regulation in quiescent NSPCs, and highlight alternative splicing as a post-transcriptional regulatory mechanism in the transition from stem cell activation to quiescence.

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Section: Discussionmentioning

confidence: 98%

Section: Lef1 Binding Motifs Enriched In Nspc Enhancers and Putative ...mentioning

confidence: 99%

The transcription factor LEF1 interacts with NFIX and switches isoforms during adult hippocampal neural stem cell quiescence

García-Corzo

Calatayud-Baselga

Casares-Crespo

et al. 2022

Front. Cell Dev. Biol.

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“…However, downstream targets of the Notch pathway (Hes and Hey transcription factors) are only expressed by NSCs. This indicates that Notch signaling in the neurogenic niches is highly regulated and not only due to receptor or ligand expression by a cell (Figure 2A; Stump et al, 2002;Irvin et al, 2004;Nyfeler et al, 2005;Carlen et al, 2009;Aguirre et al, 2010;Lugert et al, 2010;Basak et al, 2012;Kawaguchi et al, 2013;Lavado and Oliver, 2014;Ehret et al, 2015;Kawai et al, 2017;Semerci et al, 2017;Engler et al, 2018a,b;Zhang et al, 2018;Sueda et al, 2019;Zhang et al, 2019;Harada et al, 2021). Notch signaling can be regulated at multiple levels modulating the strength and dynamics of the signal outcome.…”

Section: Notch Signaling In Adult Neurogenesismentioning

confidence: 96%

“…Expression of all four Notch receptor paralogs has been documented in various cell types of the adult mouse brain including by NSCs (Notch1, Notch2 and Notch3), astrocytes (Notch1 and Notch2), neurons (Notch1 and Notch2), endothelial cells (Notch1 and Notch4) and vascular smooth muscle cells and pericytes (Notch3) (Basak et al, 2012;Ehret et al, 2015;Llorens-Bobadilla et al, 2015;Shin et al, 2015;Kawai et al, 2017;Rieskamp et al, 2018;Engler et al, 2018a;Zhang et al, 2019;Ho et al, 2020). Furthermore, Notch receptors and many of their ligands are expressed by NSCs, progenitors and neuroblasts throughout the adult neurogenic lineage.…”

Section: Notch Signaling In Adult Neurogenesismentioning

confidence: 99%

Notch signaling as a master regulator of adult neurogenesis

Lampada

Taylor

2023

Front. Neurosci.

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Neurogenesis ceases in most regions of the mammalian brain before or shortly after birth, however, in a few restricted brain regions, the production of new neurons proceeds into adulthood. Neural stem cells (NSCs) in these neurogenic zones are integrated into niches that control their activity and fate. Most stem cells in the adult brain are mitotically inactive and these cells can remain quiescent for months or even years. One of the key questions is what are the molecular mechanisms that regulate NSC maintenance and differentiation. Notch signaling has been shown to be a critical regulator of stem cell activity and maintenance in many tissues including in the nervous system. In this mini-review we discuss the roles of Notch signaling and the functions of the different Notch receptors and ligands in regulating neurogenesis in the adult murine brain. We review the functions of Notch signaling components in controlling NSC quiescence and entry into cell cycle and neurogenesis.

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“…In the Notch2 conditional KO, Id4 expression was significantly reduced, while forced Id4 expression induced differentiation towards the astrocyte lineage. Thus, Notch2 acts to maintain quiescence and includes Id4 as the main downstream regulator together with Hes1/Hes5 expression induction, which then represses the pro-neural TF Ascl1 and maintains NSCs in the dormant state (Zhang et al, 2019).…”

Section: Early Events: From Stemness and Proliferation To Cell Fate D...mentioning

confidence: 99%

Endogenous neural stem cells characterization using omics approaches: Current knowledge in health and disease

Murtaj

Butti

Martino

et al. 2023

Front. Cell. Neurosci.

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Neural stem cells (NSCs), an invaluable source of neuronal and glial progeny, have been widely interrogated in the last twenty years, mainly to understand their therapeutic potential. Most of the studies were performed with cells derived from pluripotent stem cells of either rodents or humans, and have mainly focused on their potential in regenerative medicine. High-throughput omics technologies, such as transcriptomics, epigenetics, proteomics, and metabolomics, which exploded in the past decade, represent a powerful tool to investigate the molecular mechanisms characterizing the heterogeneity of endogenous NSCs. The transition from bulk studies to single cell approaches brought significant insights by revealing complex system phenotypes, from the molecular to the organism level. Here, we will discuss the current literature that has been greatly enriched in the “omics era”, successfully exploring the nature and function of endogenous NSCs and the process of neurogenesis. Overall, the information obtained from omics studies of endogenous NSCs provides a sharper picture of NSCs function during neurodevelopment in healthy and in perturbed environments.

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Notch2 signaling regulates Id4 and cell cycle genes to maintain neural stem cell quiescence in the adult hippocampus

Cited by 4 publications

References 54 publications

The transcription factor LEF1 interacts with NFIX and switches isoforms during adult hippocampal neural stem cell quiescence

The transcription factor LEF1 interacts with NFIX and switches isoforms during adult hippocampal neural stem cell quiescence

Notch signaling as a master regulator of adult neurogenesis

Endogenous neural stem cells characterization using omics approaches: Current knowledge in health and disease

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