Neural differentiation, selection and transcriptomic profiling of human neuromesodermal progenitors-like cells in vitro

Verrier, Laure; Davidson, L. S. P.; Gierliński, Marek; Dady, Alwyn; Storey, Kate G.

doi:10.1242/dev.166215

Cited by 55 publications

(93 citation statements)

References 67 publications

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“…According to this idea, NMPs contribute to trunk neurons, such as spinal motor neurons, during body/tail elongation. Generation and characterization of trunk neural cell types through NMPs is a topic of wide interest with the potential for therapeutic application (Gouti et al, 2015;Verrier et al, 2018). Recent reports demonstrated that manipulation of retinoic acid, hedgehog and BMP/TGFβ signaling can alter neural differentiation from NMPs (Cunningham et al, 2016;Gouti et al, 2014;Lippmann et al, 2015;Verrier et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…Generation and characterization of trunk neural cell types through NMPs is a topic of wide interest with the potential for therapeutic application (Gouti et al, 2015;Verrier et al, 2018). Recent reports demonstrated that manipulation of retinoic acid, hedgehog and BMP/TGFβ signaling can alter neural differentiation from NMPs (Cunningham et al, 2016;Gouti et al, 2014;Lippmann et al, 2015;Verrier et al, 2018). Therefore, accelerated neural patterning and differentiation in the absence of Sall4 in NMPs and their descendants offer a possibility of manipulating neural differentiation in vitro through regulating functions of Sall4 in combination with these signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

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Sall4 regulates neuromesodermal progenitors and their descendants during body elongation in mouse embryos

et al. 2019

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Bi-potential neuromesodermal progenitors (NMPs) produce both neural and paraxial mesodermal progenitors in the trunk and tail during vertebrate body elongation. We show that Sall4, a pluripotency-related transcription factor gene, has multiple roles in regulating NMPs and their descendants in post-gastrulation mouse embryos. Sall4 deletion using TCre caused body/tail truncation, reminiscent of early depletion of NMPs, suggesting a role of Sall4 in NMP maintenance. This phenotype became significant at the time of the trunk-to-tail transition, suggesting that Sall4 maintenance of NMPs enables tail formation. Sall4 mutants exhibit expanded neural and reduced mesodermal tissues, indicating a role of Sall4 in NMP differentiation balance. Mechanistically, we show that Sall4 promotion of WNT/β-catenin signaling contributes to NMP maintenance and differentiation balance. RNA-Seq and SALL4 ChIP-Seq analyses support the notion that Sall4 regulates both mesodermal and neural development. Furthermore, in the mesodermal compartment, genes regulating presomitic mesoderm differentiation are downregulated in Sall4 mutants. In the neural compartment, we show that differentiation of NMPs towards post-mitotic neuron is accelerated in Sall4 mutants. Our results collectively provide evidence supporting the role of Sall4 in regulating NMPs and their descendants.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Sall4 regulates neuromesodermal progenitors and their descendants during body elongation in mouse embryos

et al. 2019

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“…We reasoned that the use of human ESCs, with the slower progression to neural progenitor cell identity, would provide a better temporal resolution of mechanisms mediating neural differentiation. To this end, we directed the differentiation of human ESCs towards spinal cord [13, 64] (Figure 2A). This regime involved the generation of NMP-like cells on day 3 (NMP-L D3), characterised by the co-expression of BRA and SOX2 and their differentiation into PAX6 expressing neural progenitors by day 8 (NP D8), which also transcribed the known PRC target HOXD11 (Figures B-B’’’).…”

Section: Resultsmentioning

confidence: 99%

ERK1/2 signalling dynamics promote neural differentiation by regulating the polycomb repressive complex

Metzis

Patel³

et al. 2019

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22 23 24 25 26 2 Abstract 27Fibroblast Growth Factor (FGF) is a neural inducer in many vertebrate embryos, but how it regulates 28 chromatin organization to coordinate the activation of neural genes is unclear. Moreover, for 29 differentiation to progress FGF signalling has to decline. Why this signalling dynamic is required has not 30 been determined. Here we show that dephosphorylation of the FGF effector kinase ERK1/2 rapidly 31 increases chromatin accessibility at neural genes in mouse embryos and, using ATAC-seq in human 32 embryonic stem cell derived spinal cord precursors, we demonstrate that this occurs across hundreds of 33 neural genes. Importantly, while Erk1/2 inhibition induces precocious neural gene transcription, this step 34 involves dissociation of the polycomb repressive complex from gene loci and takes places independently 35 of subsequent loss of the repressive histone mark H3K27me3 and transcriptional onset. We find that loss 36 of ERK1/2 activity but not its occupancy at neural genes is critical for this mechanism. Moreover, transient 37 ERK1/2 inhibition is sufficient for polycomb protein dissociation and this is not reversed on resumption 38 of ERK1/2 signalling. These data indicate that ERK1/2 signalling maintains polycomb repressive complexes 39 at neural genes, that its decline coordinates their increased accessibility and that this is a directional 40 molecular mechanism, which initiates the process of neural commitment. Furthermore, as the polycomb 41 repressive complexes repress but also ready genes for transcription, these findings suggest that ERK1/2 42 promotion of these complexes is a rite of passage for subsequent differentiation. 43 involvement of ERK1/2 signalling in this process. Rather than promoting differentiation however, 69 inhibition of ERK1/2 activity in mouse ES cells supports pluripotency [24, 25] and exposure to FGF/ERK1/2 70 signalling appears here to be an initial step towards differentiation. In agreement with this, FGF is 71 required for neural differentiation of mES cells [26][27][28] although the timing of this requirement differs 72 between assays [29]. Importantly, however, only a short critical period of ERK1/2 signalling is required in 73 mES cells for subsequent expression of neural genes [27], after which FGF inhibition then accelerates 74 neural differentiation [27, 30, 31]. Moreover, in mouse epiblast stem cells (mEpiSC), which rely on FGF 75 for self-renewal, prolonged FGF signaling abrogates neural differentiation [32]. Consistent with this in 76 both mEpiSCs and human ES cells (which also depend on FGF for self-renewal), inhibition of FGF/ERK1/2 77 signalling promotes neural differentiation [30, 32]. These findings indicate that temporal control over 78 FGF/ERK1/2 signalling is instrumental in the estabishment of neural identity from epiblast cell precursors. 79 A clue to the mechanism by which FGF regulates neural differentiation was revealed by analysis 80 of chromatin organisation at key neural progenitor genes in the mouse embryo CLE [33]. This...

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“…While the transcriptomes of the neural stem zones and of the putative neuromesodermal precursors have been explored (Gouti et al, 2017;Verrier et al, 2018), the mesodermal stem zone is poorly characterised. As a prerequisite to assess the molecular identity of cells in posterior stem zones in functional experiments, we first sought to identify a specific molecular identity of MSZ, distinct from both the surrounding neural plate and the more caudal PS that continues to gastrulate.…”

Section: A Unique Molecular Profile Of the Mesodermal Stem Zonementioning

confidence: 99%

Neuromesodermal progenitors separate the axial stem zones while producing few single- and dual-fated descendants

Kyrsting

Stegmaier

et al. 2019

Preprint

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Most embryos and regenerating tissues grow by the action of stem zones. Two epithelial stem zones drive axial elongation in amniotes: the mature organizer generates mesoderm, the neuralised ectoderm around it extends the neuraxis. Bipotential progenitors were also shown to exist. How are these stem cell populations organised and what controls the cell fate of bipotential progenitors? We use direct, in vivo imaging of these stem cells in the chick. We find that progenitors of single and dual fates are mingled in a small region between the specialised stem zones. Divergent tissue movements surround this region. When transplanted downstream of these flows, cells from the region of mixed fates adopt the molecular identity and behaviour of the target stem zone, irrespective of their normal fate. Thus, multipotent cells serve to separate the specialized stem zones, instead of a classical boundary. We propose their fate is determined extrinsically by morphogenetic shearing.

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Neural differentiation, selection and transcriptomic profiling of human neuromesodermal progenitors-like cells in vitro

Cited by 55 publications

References 67 publications

Sall4 regulates neuromesodermal progenitors and their descendants during body elongation in mouse embryos

Sall4 regulates neuromesodermal progenitors and their descendants during body elongation in mouse embryos

ERK1/2 signalling dynamics promote neural differentiation by regulating the polycomb repressive complex

Neuromesodermal progenitors separate the axial stem zones while producing few single- and dual-fated descendants

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