Cell Fate Decisions in the Neural Crest, from Pigment Cell to Neural Development

Dawes, Jonathan; Kelsh, Robert N.

doi:10.3390/ijms222413531

Cited by 4 publications

(6 citation statements)

References 156 publications

(223 reference statements)

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“…However, lineage-tracing of ltk- expressing cells reveals their multipotency extends beyond pigment cell-types to neural fates. We conclude that pigment cell development does not involve a conventional PFR mechanism, but instead occurs directly and more dynamically from a broadly multipotent intermediate state, reconciling the DFR and PFR models and consistent with our recently-proposed Cyclical Fate Restriction (CFR) model 29 , 30 . We propose that single cell RNA-sequencing (scRNA-seq) studies nicely document these dynamic changes in fate specification and differentiation, but often underestimate fate potential of these cells.…”

Section: Introductionsupporting

confidence: 85%

“…We conclude that whilst these studies document changing transcriptional profiles associated with differentiation in great detail, likely reflecting the environmental signals the cells encounter, they are less well-equipped to assess the retained potency of these cells. Taken together, these data and our NanoString profiles suggest a more dynamic situation than strictly envisaged in the DFR and PFR models, where NCCs retain high multipotency, whilst becoming biased towards specific fates by environmental signals; we have recently proposed a Cyclical Fate Restriction (CFR) hypothesis to reconcile these observations 29 , 30 .…”

Section: Resultsmentioning

confidence: 51%

“…To reconcile our observations with those underpinning the PFR model, we propose a Cyclical Fate Restriction (CFR) model in which our broadly multipotent intermediate is transcriptionally dynamic, transitioning between sub-states, each of which is likely biased towards a subset of derivative fates, but also under substantial control by environmental factors, so that the dwell-time in each biased substate may be extended or minimized appropriately (Fig. 4d ; described in detail in 29 , 30 , 63 ). We propose that heterogeneity of HMP cells results from the intrinsically dynamic nature of their gene regulatory network (GRN), but also the influence of those environmental signals.…”

Section: Discussionmentioning

confidence: 91%

“…In mouse and chick, shared progenitors for melanocytes and glia have been proposed 25 , 26 , and whilst in mouse migrating NC cells retain multipotency (defined there as at least bipotency) 27 , neural derivatives appear to originate via a PFR mechanism involving bipotent neuroglial progenitors 28 . However, distinguishing cells that are restricted to a subset of fates from those specified to those fates is non-trivial in vivo 18 , 19 , 29 , 30 . Transcriptional profiling of cells identifies cell specification state, defined as being where cells show expression of one or more characteristic markers for that fate, but until recently, this was judged by one or two markers at a time, leaving unclear whether the same cells also showed specification towards other fates too.…”

Section: Introductionmentioning

confidence: 99%

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Zebrafish pigment cells develop directly from persistent highly multipotent progenitors

et al. 2023

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Neural crest cells are highly multipotent stem cells, but it remains unclear how their fate restriction to specific fates occurs. The direct fate restriction model hypothesises that migrating cells maintain full multipotency, whilst progressive fate restriction envisages fully multipotent cells transitioning to partially-restricted intermediates before committing to individual fates. Using zebrafish pigment cell development as a model, we show applying NanoString hybridization single cell transcriptional profiling and RNAscope in situ hybridization that neural crest cells retain broad multipotency throughout migration and even in post-migratory cells in vivo, with no evidence for partially-restricted intermediates. We find that leukocyte tyrosine kinase early expression marks a multipotent stage, with signalling driving iridophore differentiation through repression of fate-specific transcription factors for other fates. We reconcile the direct and progressive fate restriction models by proposing that pigment cell development occurs directly, but dynamically, from a highly multipotent state, consistent with our recently-proposed Cyclical Fate Restriction model.

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Section: Introductionsupporting

confidence: 85%

Section: Resultsmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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Zebrafish pigment cells develop directly from persistent highly multipotent progenitors

et al. 2023

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“…For further details of our specific model system, we refer the reader to recent papers [16,[20][21][22] which summarize the biological background, recent experimental work and mathematical modelling. Here, our focus is purely on the potential for the oscillatory nature of developmental trajectories to destabilize pseudotime reconstruction methodologies, and not on the specific biological details of this model gene regulatory system.…”

Section: Introductionmentioning

confidence: 99%

Oscillatory differentiation dynamics fundamentally restricts the resolution of pseudotime reconstruction algorithms

Vo,

Dawes,

Kelsh

2024

J. R. Soc. Interface.

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The challenge to understand differentiation and cell lineages in development has resulted in many bioinformatics software tools, notably those working with gene expression data obtained via single-cell RNA sequencing obtained at snapshots in time. Reconstruction methods for trajectories often proceed by dimension reduction, data clustering and then computation of a tree graph in which edges indicate closely related clusters. Cell lineages can then be deduced by following paths through the tree. In the case of multi-potent cells undergoing differentiation, this trajectory reconstruction involves the reconstruction of multiple distinct lineages corresponding to commitment to each of a set of distinct fates. Recent work suggests that there may be cases in which the cell differentiation process involves trajectories that explore, in a dynamic and oscillatory fashion, propensity to differentiate into a number of possible cell fates before commitment finally occurs. Here, we show theoretically that the presence of such oscillations provides intrinsic constraints on the quality and resolution of the trajectory reconstruction process, even for idealized noise-free data. These constraints point to inherent common limitations of current methodologies and serve both to provide additional challenge in the development of software tools and also may help to understand features observed in recent experiments.

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Neural Crest: Origin, Migration and Differentiation

Sutton¹,

Kelsh²

2022

Encyclopedia of Life Sciences

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The neural crest is a population of cells that emigrates from the dorsal neural tube during early embryogenesis and migrates extensively to give rise to a myriad of cell types. Patterns of migration are controlled largely by extracellular cues in the environment. Neural crest cells are initially multipotent, but the mechanism whereby cells choose and become committed to individual fates remains a longstanding source of contention. Cell fate specification – the selection of an individual cell fate from all the possibilities available to a multipotent progenitor – is generally considered to be a progressive process. However, a recent flurry of single‐cell transcriptional profiling studies indicates a more dynamic process in which cells with retained multipotency display expression of competing genetic modules specifying different fates. Extracellular cues in the migratory and postmigratory environment act together with intrinsic transcription factors to ensure that specific fates are chosen. Key Concepts The neural crest is an important tissue, as reflected in its nickname, ‘the fourth germ layer’. Neural crest cells give rise to many different cell types. Neural crest cells are induced at the boundary of the developing neural plate and prospective epidermis. Neural crest induction depends on BMP signalling in the prospective epidermis and Wnt signalling from the underlying mesoderm. These signals induce neural crest in two phases, specification of the neural plate border, and specification/maintenance of definitive neural crest. Neural crest migration patterns are complex, and usually specific to the derivative fate adopted. Neural crest migration is controlled by the environmental distribution of repellent and attractive/permissive signals, with specific receptor expression in the neural crest cells determining their response. All neural crest cells are initially multipotent, with specification of individual derivative fates resulting from competition between genetic modules controlling pairs of fates. Nevertheless, it is proposed that these specified cells retain a cryptic full multipotency, most visible in adult neural crest‐derived stem cells. Neural crest fate specification is then a dynamic process in which extracellular factors influence the transcriptional state of the cell, eventually driving it towards a specific fate choice. Fate specification results from transcriptional activation of key genes encoding (a combination of) specific transcription factors. These transcription factors, together with ongoing extracellular signals, activate and maintain the fate‐specific gene regulatory networks that characterise each cell type.

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Cell Fate Decisions in the Neural Crest, from Pigment Cell to Neural Development

Cited by 4 publications

References 156 publications

Zebrafish pigment cells develop directly from persistent highly multipotent progenitors

Zebrafish pigment cells develop directly from persistent highly multipotent progenitors

Oscillatory differentiation dynamics fundamentally restricts the resolution of pseudotime reconstruction algorithms

Neural Crest: Origin, Migration and Differentiation

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