Single-cell atlas of early chick development reveals gradual segregation of neural crest lineage from the neural plate border during neurulation

Williams, Ruth M.; Lukoseviciute, Martyna; Sauka‐Spengler, Tatjana; Bronner‐Fraser, Marianne

doi:10.7554/elife.74464

Cited by 39 publications

(44 citation statements)

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“…Nevertheless, our understanding as to how individual cells undergo cell fate decisions has been limited by our inability to study transcription and gene regulation at a single cell level. Recent studies have demonstrated that in contrast to what was previously thought, cells co-express markers that specify either placodal, neural or neural crest fates, even during late neurulation (Roellig et al, 2017;Williams et al, 2022). This newly characterised cellular heterogeneity requires us to revisit models for cell fate specification at the NPB and reconsider our definition of the NPB cell state itself.…”

Section: Discussionmentioning

confidence: 91%

“…NPB cells are thought to retain the potential to give rise to neural, neural crest and placodal lineages, and recent single cell analysis suggests that they can do so even at late neurulation stages (Roellig et al, 2017; Williams et al, 2022). So far, our analysis reveals an early NPB cell population identified by the overlapping expression of non-neural and early neural markers at primitive streak stages, albeit being transcriptionally highly heterogeneous.…”

Section: Resultsmentioning

confidence: 99%

“…Secondly, the NPB is a transitory state through which cells are thought to pass prior to acquisition of any of the four ectodermal fates (neural, neural crest, placodal and epidermal). Finally, cells at the NPB appear to be highly heterogeneous, with precursors for the different ectodermal fates found intermingled, even at late stages of neurulation (Bhattacharyya et al, 2004; Roellig et al, 2017; Streit, 2002; Williams et al, 2022). To overcome these challenges, we categorised cells using a binary knowledge matrix based on expression data obtained from the literature (Supplementary File 1).…”

Section: Resultsmentioning

confidence: 99%

“…Recent studies in chick have begun to explore these questions. Single cell analysis at the NPB reveals considerable heterogeneity of gene expression: factors previously thought to be fate-specific are co-expressed in individual cells even as late as neural tube stages (Roellig et al, 2017; Williams et al, 2022). Furthermore, lineage tracing using a ‘neural-specific’ Sox2 enhancer shows that Sox2 + cells can contribute not only to neural tissue but also to neural crest and epidermis (Roellig et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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A gradient border model for cell fate decisions at the neural plate border

Thiery

Buzzi

Hamrud

et al. 2022

Preprint

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The vertebrate neural plate border is a transient territory at the edge of the neural plate containing precursors for all ectodermal derivatives: the neural plate, neural crest, placodes, and epidermis. Elegant functional experiments in a range of vertebrate models have provided an in-depth understanding of gene regulatory interactions within the ectoderm. However, these experiments conducted at tissue level have raised seemingly contradictory models for fate allocation of individual cells. Here, we carry out single cell RNA sequencing of chick ectoderm from primitive streak to neurulation stage, to explore cell state diversity and heterogeneity. We identify and characterise the dynamics of gene modules containing key factors known to regulate ectodermal cell fates, allowing us to model the order in which these fates are specified. Furthermore, we find that genes previously classified as neural plate border specifiers typically exhibit dynamic expression patterns and are biased towards either placodal or neural crest fates. Instead, given its transient and heterogenous characteristics, the neural plate border should be defined based on the co-expression of alternative placodal and neural crest gene modules. Finally, we propose a gradient border model for cell fate choice at the neural plate border, with the probability of cell fate allocation closely tied to the spatiotemporal positioning of cells.

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Section: Discussionmentioning

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A gradient border model for cell fate decisions at the neural plate border

Thiery

Buzzi

Hamrud

et al. 2022

Preprint

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“…Similarly, Pax7 mRNA and protein are both strongly upregulated and expanded dorsally into the Pax3-only expression domain in Pax3 null ( Sp allele) embryonic neural tube and somites, suggesting that Pax3 may normally function to repress Pax7 [ 16 ]. However, despite Pax7 being one of the earliest markers of avian neural crest [ 17 ] and Pax7 Cre /R26 YFP lineage mapping showing some mammalian neural crest contribution [ 18 ], Pax7 is not thought to play a major functional role in mouse heart morphogenesis [ 11 ]. Interestingly, Pax3 (Pax3 Δ5 )/Pax7 (Pax7 Δ2 ) double heterozygotes exhibit a gain-of-function phenotype, as 40% of double heterozygotes develop postnatal hydrocephalus, which is not seen in either single heterozygote [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Pax3 Hypomorphs Reveal Hidden Pax7 Functional Genetic Compensation in Utero

Zhou

Conway

2022

JDB

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Pax3 and Pax7 transcription factors are paralogs within the Pax gene family that that are expressed in early embryos in partially overlapping expression domains and have distinct functions. Significantly, mammalian development is largely unaffected by Pax7 systemic deletion but systemic Pax3 deletion results in defects in neural tube closure, neural crest emigration, cardiac outflow tract septation, muscle hypoplasia and in utero lethality by E14. However, we previously demonstrated that Pax3 hypomorphs expressing only 20% functional Pax3 protein levels exhibit normal neural tube and heart development, but myogenesis is selectively impaired. To determine why only some Pax3-expressing cell lineages are affected and to further titrate Pax3 threshold levels required for neural tube and heart development, we generated hypomorphs containing both a hypomorphic and a null Pax3 allele. This resulted in mutants only expressing 10% functional Pax3 protein with exacerbated neural tube, neural crest and muscle defects, but still a normal heart. To examine why the cardiac neural crest appears resistant to very low Pax3 levels, we examined its paralog Pax7. Significantly, Pax7 expression is both ectopically expressed in Pax3-expressing dorsal neural tube cells and is also upregulated in the Pax3-expressing lineages. To test whether this compensatory Pax7 expression is functional, we deleted Pax7 both systemically and lineage-specifically in hypomorphs expressing only 10% Pax3. Removal of one Pax7 allele resulted in partial outflow tract defects, and complete loss of Pax7 resulted in full penetrance outflow tract defects and in utero lethality. Moreover, combinatorial loss of Pax3 and Pax7 resulted in severe craniofacial defects and a total block of neural crest cell emigration from the neural tube. Pax7Cre lineage mapping revealed ectopic labeling of Pax3-derived neural crest tissues and within the outflow tract of the heart, experimentally confirming the observation of ectopic activation of Pax7 in 10% Pax3 hypomorphs. Finally, genetic cell ablation of Pax7Cre-marked cells is sufficient to cause outflow tract defects in hypomorphs expressing only 10% Pax3, confirming that ectopic and induced Pax7 can play an overlapping functional genetic compensational role in both cardiac neural crest lineage and during craniofacial development, which is normally masked by the dominant role of Pax3.

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Dysregulation of Grainyhead‐like 3 expression causes widespread developmental defects

Deng

Butt

Arhatari

et al. 2023

Developmental Dynamics

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The gene encoding the transcription factor, Grainyhead-like 3 (Grhl3), plays critical roles in mammalian development and homeostasis, and these have been uncovered through analysis of loss-of-function models. Grhl3-null embryos exhibit a range of gross phenotypes including a shortened longitudinal axis, thoraco-lumbo-sacral spina bi da and soft-tissue syndactyly. Additional studies reveal that these embryos also exhibit a proliferation/differentiation imbalance in the epidermis. This manifests as a failure in skin barrier formation resulting in peri-natal lethality, and defective wound repair. Conditional inactivation of Grhl3 in the squamous epithelium of adult skin, head and neck tissues, and oesophagus reproduces this proliferation/differentiation imbalance and leads to squamous cell carcinomas. These observations establish GRHL3 as a critical tumour suppressor. Despite these extensive analyses of Grhl3 loss-of-function models, the consequences of gain-of-function of this gene have been di cult to achieve.We have redressed this issue through the generation of a novel mouse model that expresses Grhl3 from a transgene integrated in the Rosa26 locus on an endogenous Grhl3-null background. Expression of the transgene rescues both the neurulation and skin barrier defects of the knockout mice, allowing survival into adulthood. Despite this, the mice are not normal, exhibiting a range of phenotypes attributable to dysregulated Grhl3 expression. In mice homozygous for the transgene, we observe a severe Shaker-Waltzer phenotype associated with hearing impairment. Micro-CT scanning of the cochleae and the vestibular apparatus revealed profound structural alterations underlying these phenotypes. In addition, these mice exhibit other developmental anomalies including hair loss, digit defects and epidermal dysmorphogenesis. These ndings indicate that diverse developmental processes display low tolerance to dysregulation of Grhl3.

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Single-cell atlas of early chick development reveals gradual segregation of neural crest lineage from the neural plate border during neurulation

Cited by 39 publications

References 54 publications

A gradient border model for cell fate decisions at the neural plate border

A gradient border model for cell fate decisions at the neural plate border

Pax3 Hypomorphs Reveal Hidden Pax7 Functional Genetic Compensation in Utero

Dysregulation of Grainyhead‐like 3 expression causes widespread developmental defects

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