Loss of FGF-Dependent Mesoderm Identity and Rise of Endogenous Retinoid Signalling Determine Cessation of Body Axis Elongation

Olivera-Martínez, Isabel; Harada, Hirofumi; Halley, Pamela A.; Storey, Kate G.

doi:10.1371/journal.pbio.1001415

Cited by 162 publications

(203 citation statements)

References 79 publications

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“…We observed that cells in the NMP domain of the posterior wall of the tailbud adhere to each other and to the border between the epidermis and the NMP population along the apical edge of the NMPs. In a process that appears strikingly similar to that described in a recent report of mouse epiblast cells undergoing EMT to form mesoderm during gastrulation (Ramkumar et al, 2016), individual cells were observed to undergo apical constriction, ingression, and epithelial layer exit, while remaining tethered to the epithelial layer by a long apical extension of the membrane for a period of time before complete dissociation (Fig. 7A,B, Movies 1 and 2).…”

Section: High-resolution Imaging Of the Tailbud Emtsupporting

confidence: 80%

“…1L,M). Tailbud NMPs are characterized by the co-expression of ntla and sox2 Olivera-Martinez et al, 2012). Similar to ntla, sox2 expression in the tailbud was expanded after loss of FGF signaling (Fig.…”

Section: Fgf Signaling Is Required For Pm Induction From Nmpsmentioning

confidence: 94%

“…7M). In the chick, temporal loss of FGF signaling causes a loss of brachyury expression in the tailbud (Olivera-Martinez et al, 2012) 24 h after signal inhibition. Our experiments showed expanded ntla expression in the tailbud analyzed in embryos just 3 h after FGF inhibition.…”

Section: High-resolution Imaging Of the Tailbud Emtmentioning

confidence: 99%

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FGF and canonical Wnt signaling cooperate to induce paraxial mesoderm from tailbud neuromesodermal progenitors through regulation of a two-step epithelial to mesenchymal transition

et al. 2017

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Mesoderm induction begins during gastrulation. Recent evidence from several vertebrate species indicates that mesoderm induction continues after gastrulation in neuromesodermal progenitors (NMPs) within the posteriormost embryonic structure, the tailbud. It is unclear to what extent the molecular mechanisms of mesoderm induction are conserved between gastrula and post-gastrula stages of development. Fibroblast growth factor (FGF) signaling is required for mesoderm induction during gastrulation through positive transcriptional regulation of the T-box transcription factor brachyury. We find in zebrafish that FGF is continuously required for paraxial mesoderm (PM) induction in post-gastrula NMPs. FGF signaling represses the NMP markers brachyury (ntla) and sox2 through regulation of tbx16 and msgn1, thereby committing cells to a PM fate. FGF-mediated PM induction in NMPs functions in tight coordination with canonical Wnt signaling during the epithelial to mesenchymal transition (EMT) from NMP to mesodermal progenitor. Wnt signaling initiates EMT, whereas FGF signaling terminates this event. Our results indicate that germ layer induction in the zebrafish tailbud is not a simple continuation of gastrulation events.

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Section: High-resolution Imaging Of the Tailbud Emtsupporting

confidence: 80%

Section: Fgf Signaling Is Required For Pm Induction From Nmpsmentioning

confidence: 94%

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FGF and canonical Wnt signaling cooperate to induce paraxial mesoderm from tailbud neuromesodermal progenitors through regulation of a two-step epithelial to mesenchymal transition

et al. 2017

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“…FGF signalling is required for convergence and extension, but not posterior volumetric growth in zebrafish FGF signalling is known to be important for posterior body elongation across vertebrates (Bénazéraf et al, 2010;Bouldin et al, 2014;del Corral and Storey, 2004;Olivera-Martinez et al, 2012;Lawton et al, 2013). We applied our morphometric approach to determine whether FGF signalling plays a role in volumetric growth and/or convergence during posterior body elongation in zebrafish.…”

Section: Differential Tissue Contributions To Both Volumetric Growth mentioning

confidence: 99%

Species tailoured contribution of volumetric growth and tissue convergence to posterior body elongation in vertebrates

et al. 2016

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Posterior body elongation is a widespread mechanism propelling the generation of the metazoan body plan. The posterior growth model predicts that a posterior growth zone generates sufficient tissue volume to elongate the posterior body. However, there are energy supply-related differences between vertebrates in the degree to which growth occurs concomitantly with embryogenesis. By applying a multi-scalar morphometric analysis in zebrafish embryos, we show that posterior body elongation is generated by an influx of cells from lateral regions, by convergence-extension of cells as they exit the tailbud, and finally by a late volumetric growth in the spinal cord and notochord. Importantly, the unsegmented region does not generate additional tissue volume. Fibroblast growth factor inhibition blocks tissue convergence rather than volumetric growth, showing that a conserved molecular mechanism can control convergent morphogenesis through different cell behaviours. Finally, via a comparative morphometric analysis in lamprey, dogfish, zebrafish and mouse, we propose that elongation via posterior volumetric growth is linked to increased energy supply and is associated with an overall increase in volumetric growth and elongation.

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“…The physiological significance of RARγ expression in the embryonic posterior is uncertain. RARγ might function to terminate the body axis at late stages by inducing apoptosis (Olivera-Martinez et al, 2012), but that model would not explain the strong expression of RARγ observed at neurula, continuing through tailbud stages, despite the apparent absence of RA.…”

Section: Introductionmentioning

confidence: 98%

Active repression by RARγ signaling is required for vertebrate axial elongation

et al. 2014

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Retinoic acid receptor gamma 2 (RARγ2) is the major RAR isoform expressed throughout the caudal axial progenitor domain in vertebrates. During a microarray screen to identify RAR targets, we identified a subset of genes that pattern caudal structures or promote axial elongation and are upregulated by increased RARmediated repression. Previous studies have suggested that RAR is present in the caudal domain, but is quiescent until its activation in late stage embryos terminates axial elongation. By contrast, we show here that RARγ2 is engaged in all stages of axial elongation, not solely as a terminator of axial growth. In the absence of RA, RARγ2 represses transcriptional activity in vivo and maintains the pool of caudal progenitor cells and presomitic mesoderm. In the presence of RA, RARγ2 serves as an activator, facilitating somite differentiation. Treatment with an RARγ-selective inverse agonist (NRX205099) or overexpression of dominant-negative RARγ increases the expression of posterior Hox genes and that of marker genes for presomitic mesoderm and the chordoneural hinge. Conversely, when RAR-mediated repression is reduced by overexpressing a dominant-negative co-repressor (c-SMRT), a constitutively active RAR (VP16-RARγ2), or by treatment with an RARγ-selective agonist (NRX204647), expression of caudal genes is diminished and extension of the body axis is prematurely terminated. Hence, gene repression mediated by the unliganded RARγ2-co-repressor complex constitutes a novel mechanism to regulate and facilitate the correct expression levels and spatial restriction of key genes that maintain the caudal progenitor pool during axial elongation in Xenopus embryos.

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Loss of FGF-Dependent Mesoderm Identity and Rise of Endogenous Retinoid Signalling Determine Cessation of Body Axis Elongation

Abstract: By analyzing cellular and molecular changes in key cell populations in the tailbud during embryogenesis, this work uncovers critical signaling events that determine vertebrate body length.

Cited by 162 publications

References 79 publications

FGF and canonical Wnt signaling cooperate to induce paraxial mesoderm from tailbud neuromesodermal progenitors through regulation of a two-step epithelial to mesenchymal transition

FGF and canonical Wnt signaling cooperate to induce paraxial mesoderm from tailbud neuromesodermal progenitors through regulation of a two-step epithelial to mesenchymal transition

Species tailoured contribution of volumetric growth and tissue convergence to posterior body elongation in vertebrates

Active repression by RARγ signaling is required for vertebrate axial elongation

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