Neurogenic differentiation by hippocampal neural stem and progenitor cells is biased by NFIX expression

Harris, Lachlan; Zalucki, Oressia; Olivier, C; Fraser, James A.; Matuzelski, Elise; Oishi, Sabrina; Harvey, Tracey J.; Heng, Julian Ik‐Tsen; Gronostajski, Richard M.; Piper, Michael

doi:10.1242/dev.155689

Cited by 31 publications

(30 citation statements)

References 54 publications

(84 reference statements)

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“…This is supported by the increased expression of the pro-astrogliogenic transcription factor NFIA not only in NSCs but also in mitotically active progenitors of COUP-TFI-icKO Glast DG. Moreover, loss of COUP-TFI function directly in DG progenitors prompted these cells to acquire an astroglial fate indicating they might still be multipotent, as also recently suggested (Harris et al, 2018) and need COUP-TFI to restrict their potential to a neuronal fate. We thus hypothesized that the increase in astroglia at the expense of newborn neurons observed in the adult DG upon inflammation could be related to COUP-TFI downregulation.…”

Section: Discussionmentioning

confidence: 67%

Neuron-Astroglia Cell Fate Decision in the Adult Mouse Hippocampal Neurogenic Niche Is Cell-Intrinsically Controlled by COUP-TFI In Vivo

Bonzano¹,

Crisci²,

Podleśny-Drabiniok³

et al. 2018

Cell Reports

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In the dentate gyrus (DG) of the mouse hippocampus, neurogenesis and astrogliogenesis persist throughout life. Adult-born neurons and astrocytes originate from multipotent neural stem cells (NSCs) whose activity is tightly regulated within the neurogenic niche. However, the cell-intrinsic mechanisms controlling neuron-glia NSC fate choice are largely unknown. Here, we show COUP-TFI/NR2F1 expression in DG NSCs and its downregulation upon neuroinflammation. By using in vivo inducible knockout lines, a retroviral-based loss-of-function approach and genetic fate mapping, we demonstrate that COUP-TFI inactivation in adult NSCs and/or mitotic progenitors reduces neurogenesis and increases astrocyte production without depleting the NSC pool. Moreover, forced COUP-TFI expression in adult NSCs/progenitors decreases DG astrogliogenesis and rescues the neuro-astrogliogenic imbalance under neuroinflammation. Thus, COUP-TFI is necessary and sufficient to promote neurogenesis by suppressing astrogliogenesis. Our data propose COUP-TFI as a central regulator of the neuron-astroglia cell fate decision and a key modulator during neuroinflammation in the adult hippocampus.

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Section: Discussionmentioning

confidence: 67%

Neuron-Astroglia Cell Fate Decision in the Adult Mouse Hippocampal Neurogenic Niche Is Cell-Intrinsically Controlled by COUP-TFI In Vivo

Bonzano¹,

Crisci²,

Podleśny-Drabiniok³

et al. 2018

Cell Reports

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“…Moreover, while NFI motif was most highly enriched in AQ chromatin, its enrichment in AA and stable chromatin suggests that NFI factors are multifunctional in the neurogenic lineage. Supporting this finding, NFIX has been shown to function in neuroblast differentiation in the mouse hippocampus 65 . In future work, it will be important to identify the precise sequence of transcription factor binding, chromatin remodeling events, and transcriptional alterations that occur as quiescent NSCs enter the cell cycle and return to quiescence in order to fully understand how transcriptional programs are regulated to maintain the balance between NSC quiescence and activation.…”

Section: Discussionmentioning

confidence: 68%

“…Using a combination of in silico motif mining and ChIP-seq analysis, we found that the transcriptional regulators NFI and ASCL1 each bind many chromatin regions that are uniquely accessible in quiescent or activated cells, respectively. Previous studies implicated these factors as key regulators of neurogenesis in vivo and in vitro 24, 54–56, 65 . Our observation raises an important question about the relationship between chromatin alterations and transcription factor binding during stem cell activation.…”

Section: Discussionmentioning

confidence: 99%

Changing and stable chromatin accessibility supports transcriptional overhaul during neural stem cell activation

Maybury-Lewis

Brown

Yeary

et al. 2020

Preprint

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20Adult neural stem cells are largely quiescent, and require transcriptional reprogramming 21 to reenter the cell cycle and undergo neurogenesis. However, the precise mechanisms 22 that underlie the rapid transcriptional overhaul during NSC activation remain undefined. 23Here, we identify the genome-wide chromatin accessibility differences between primary 24 neural stem and progenitor cells in quiescent and activated states. We show that these 25 distinct cellular states exhibit both shared and unique chromatin profiles, which are both 26 associated with gene regulation. Interestingly, we find that accessible chromatin states 27 specific to quiescent or activated cells are active enhancers bound by pro-neurogenic 28 and quiescence factors, ASCL1 and NFI. In contrast, shared sites are gene promoters 29 harboring constitutively accessible chromatin enriched for particular core promoter 30 elements that are functionally associated with translation and metabolic functions. 31Together, our findings reveal how accessible chromatin states regulate a transcriptional 32 overhaul and drive the switch between quiescence and proliferation in NSC activation. 33 34 46In vivo, the majority of NSCs reside in a state of quiescence 10 . Quiescent NSCs (qNSCs) 47 have exited the cell cycle but can be prompted by intrinsic or extrinsic cues to "activate" 48 and re-enter the cell cycle (we refer to these cells as activated NSCs, or aNSCs). Once 49 activated, aNSCs proliferate and may return to quiescence and self-renew, or 50 differentiate into neurons or glia. Activation of qNSCs is the first critical step in 51 neurogenesis in the adult brain, and is enhanced in response to damage (e.g. stroke) or 52 environmental stimuli such as parabiosis [11][12][13] . Evidence shows that decreased 53 neurogenesis with age occurs due to reduced activation of qNSCs, senescence of the 54 NSC niche, and exhaustion of the qNSC pool [14][15][16][17] . Accumulation of qNSCs has also been 55 observed in a rodent model for neurodevelopmental disorders, suggesting that a careful 56 balance of NSC quiescence and activation is necessary for healthy cognitive function 18 . 57However, the precise mechanisms that regulate this balance and prompt qNSCs to re-58 enter the cell cycle in the healthy mammalian brain are mostly unknown. 59 60 Recent studies reported that quiescent and activated NSCs employ cell type-specific 61 mechanisms to support their functionality, including distinct metabolic states and 62 differences in proteostasis [19][20][21] . Transcriptional profiling of qNSCs and aNSCs revealed 63 both shared and distinct transcriptional signatures in the two cell types, indicating that a 64 transcriptional overhaul occurs at a subset of genes during the process of NSC 65 activation 10,19,22,23 . For example, genes involved in cell proliferation, lipid metabolism, and 66 protein homeostasis were differentially expressed in quiescent and activated NSCs. 67 Similar changes have also been observed using in vitro models of NSC quiescence and 68 activation...

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“…NFIX belongs to nuclear factor one (NFI) family of transcription factors that consists of four members (the other three are NFIA, NFIB, and NFIC) 65 . In mammals, NFIX is widely expressed in various tissues and organs, which plays a critical role in development and disease 66,67 . As a transcription factor, NFIX has a bi-phase function in regulating target expression by directly binding a consensus sequence TTGGCN 5 GCCAA or 1/2 sites (i.e., TTGGC or GCCAA) of target promoter and then controlling the target-mediated cell functions 65,67 .…”

Section: Discussionmentioning

confidence: 99%

NORFA, long intergenic noncoding RNA, maintains sow fertility by inhibiting granulosa cell death

Liu

Zhang

et al. 2020

Commun Biol

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Long intergenic non-coding RNAs (lincRNAs) have been proved to be involved in regulating female reproduction. However, to what extent lincRNAs are involved in ovarian functions and fertility is incompletely understood. Here we show that a lincRNA, NORFA is involved in granulosa cell apoptosis, follicular atresia and sow fertility. We found that NORFA was downregulated during follicular atresia, and inhibited granulosa cell apoptosis. NORFA directly interacted with miR-126 and thereby preventing it from binding to TGFBR2 3′-UTR. miR-126 enhanced granulosa cell apoptosis by attenuating NORFA-induced TGF-β signaling pathway. Importantly, a breed-specific 19-bp duplication was detected in NORFA promoter, which proved association with sow fertility through enhancing transcription activity of NORFA by recruiting transcription factor NFIX. In summary, our findings identified a candidate lincRNA for sow prolificacy, and provided insights into the mechanism of follicular atresia and female fertility.

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Neurogenic differentiation by hippocampal neural stem and progenitor cells is biased by NFIX expression

Cited by 31 publications

References 54 publications

Neuron-Astroglia Cell Fate Decision in the Adult Mouse Hippocampal Neurogenic Niche Is Cell-Intrinsically Controlled by COUP-TFI In Vivo

Neuron-Astroglia Cell Fate Decision in the Adult Mouse Hippocampal Neurogenic Niche Is Cell-Intrinsically Controlled by COUP-TFI In Vivo

Changing and stable chromatin accessibility supports transcriptional overhaul during neural stem cell activation

NORFA, long intergenic noncoding RNA, maintains sow fertility by inhibiting granulosa cell death

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