Interaction of Wnt3a, Msgn1 and Tbx6 in neural versus paraxial mesoderm lineage commitment and paraxial mesoderm differentiation in the mouse embryo

Nowotschin, Sonja; Ferrer-Vaquer, Anna; Concepcion, Daniel; Papaioannou, Virginia E.; Hadjantonakis, Anna-Katerina

doi:10.1016/j.ydbio.2012.04.012

Cited by 80 publications

(96 citation statements)

References 31 publications

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“…Interestingly, blocking Wnt/β-catenin signaling by removing β-catenin in Notoexpressing cells led to persistent strong E-cadherin expression in NPCs and reduction of notochord elongation (Ukita et al, 2009), suggesting that Wnt/β-catenin signaling also regulates EMT in the generation of NPCs at late gastrulation stages. Consistent with this, it has been reported that Wnt3a controls paraxial mesoderm formation and Tbx6 expression (Nowotschin et al, 2012). The data in that report reveal that cells modulate the expression of Wnt3a as they traverse the PS: as they enter they upregulate Wnt3a, and then subsequently downregulate Wnt3a as they exit.…”

Section: Discussionsupporting

confidence: 80%

Wnt5aandWnt11regulate mammalian anterior-posterior axis elongation

et al. 2015

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Mesoderm formation and subsequent anterior-posterior (A-P) axis elongation are fundamental aspects of gastrulation, which is initiated by formation of the primitive streak (PS). Convergent extension (CE) movements and epithelial-mesenchymal transition (EMT) are important for A-P axis elongation in vertebrate embryos. The evolutionarily conserved planar cell polarity (PCP) pathway regulates CE, and Wnts regulate many aspects of gastrulation including CE and EMT. However, the Wnt ligands that regulate A-P axis elongation in mammalian development remain unknown. Wnt11 and Wnt5a regulate axis elongation in lower vertebrates, but only Wnt5a, not Wnt11, regulates mammalian PCP signaling and A-P axis elongation in development. Here, by generating Wnt5a; Wnt11 compound mutants, we show that Wnt11 and Wnt5a play redundant roles during mouse A-P axis elongation. Both genes regulate trunk notochord extension through PCP-controlled CE of notochord cells, establishing a role for Wnt11 in mammalian PCP. We show that Wnt5a and Wnt11 are required for proper patterning of the neural tube and somites by regulating notochord formation, and provide evidence that both genes are required for the generation and migration of axial and paraxial mesodermal precursor cells by regulating EMT. Axial and paraxial mesodermal precursors ectopically accumulate in the PS at late gastrula stages in Wnt5a −/− ; Wnt11−/− embryos and these cells ectopically express epithelial cell adhesion molecules. Our data suggest that Wnt5a and Wnt11 regulate EMT by inducing p38 (Mapk14) phosphorylation. Our findings provide new insights into the role of Wnt5a and Wnt11 in mouse early development and also in cancer metastasis, during which EMT plays a crucial role.

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Section: Discussionsupporting

confidence: 80%

Wnt5aandWnt11regulate mammalian anterior-posterior axis elongation

et al. 2015

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“…As with zebrafish tbx16 mutants, loss of Tbx6 in mouse causes a reduction of Msgn1 and an increase in brachyury and Sox2 expression (Chapman and Papaioannou, 1998;Griffin and Kimelman, 2002;Nowotschin et al, 2012;Takemoto et al, 2011;our results), all supporting the close functional parallels between mouse Tbx6 and zebrafish tbx16 despite the sequence divergence (Ahn et al, 2012). It would be interesting to examine whether Msgn1 (and/or Tbx6) in the mouse is able to cell-autonomously drive cell exit from the progenitor zone as we have shown with zebrafish Tbx16.…”

Section: Comparison With Mousesupporting

confidence: 58%

“…In mouse, loss of Tbx6 causes a phenotype that closely resembles that of zebrafish tbx16 mutants, and a large tailbud of undifferentiated tissue forms (Chapman and Papaioannou, 1998;Chapman et al, 2003;Nowotschin et al, 2012). As with zebrafish tbx16 mutants, loss of Tbx6 in mouse causes a reduction of Msgn1 and an increase in brachyury and Sox2 expression (Chapman and Papaioannou, 1998;Griffin and Kimelman, 2002;Nowotschin et al, 2012;Takemoto et al, 2011;our results), all supporting the close functional parallels between mouse Tbx6 and zebrafish tbx16 despite the sequence divergence (Ahn et al, 2012).…”

Section: Comparison With Mousementioning

confidence: 57%

Wnt signaling andtbx16form a bistable switch to commit bipotential progenitors to mesoderm

et al. 2015

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Anterior to posterior growth of the vertebrate body is fueled by a posteriorly located population of bipotential neuro-mesodermal progenitor cells. These progenitors have a limited rate of proliferation and their maintenance is crucial for completion of the anterior-posterior axis. How they leave the progenitor state and commit to differentiation is largely unknown, in part because widespread modulation of factors essential for this process causes organism-wide effects. Using a novel assay, we show that zebrafish Tbx16 (Spadetail) is capable of advancing mesodermal differentiation cell-autonomously. Tbx16 locks cells into the mesodermal state by not only activating downstream mesodermal genes, but also by repressing bipotential progenitor genes, in part through a direct repression of sox2. We demonstrate that tbx16 is activated as cells move from an intermediate Wnt environment to a high Wnt environment, and show that Wnt signaling activates the tbx16 promoter. Importantly, high-level Wnt signaling is able to accelerate mesodermal differentiation cellautonomously, just as we observe with Tbx16. Finally, because our assay for mesodermal commitment is quantitative we are able to show that the acceleration of mesodermal differentiation is surprisingly incomplete, implicating a potential separation of cell movement and differentiation during this process. Together, our data suggest a model in which high levels of Wnt signaling induce a transition to mesoderm by directly activating tbx16, which in turn acts to irreversibly flip a bistable switch, leading to maintenance of the mesodermal fate and repression of the bipotential progenitor state, even as cells leave the initial highWnt environment.

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“…Genetic removal of the Wnt3a ligand (58), or conversely, ectopic activation of Wnt3a in the epiblast (59), result in severe axis truncation posterior to the forelimb. Wnt3a expression has been shown to decrease as progenitor cells commit to a paraxial mesoderm fate (60,61), and sustained Wnt activity disrupts somite formation (51) and somite polarity (59), dependent on timing and method of activation. These observations indicate that careful titration of Wnt levels is essential throughout the process of somite formation.…”

Section: Mir-196 Has the Potential To Modulate Wnt Signaling By Multiplementioning

confidence: 99%

Independent regulation of vertebral number and vertebral identity by microRNA-196 paralogs

Wong

Agarwal

Mansfield

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The Hox genes play a central role in patterning the embryonic anterior-to-posterior axis. An important function of Hox activity in vertebrates is the specification of different vertebral morphologies, with an additional role in axis elongation emerging. The miR-196 family of microRNAs (miRNAs) are predicted to extensively target Hox 3′ UTRs, although the full extent to which miR-196 regulates Hox expression dynamics and influences mammalian development remains to be elucidated. Here we used an extensive allelic series of mouse knockouts to show that the miR-196 family of miRNAs is essential both for properly patterning vertebral identity at different axial levels and for modulating the total number of vertebrae. All three miR-196 paralogs, 196a1, 196a2, and 196b, act redundantly to pattern the midthoracic region, whereas 196a2 and 196b have an additive role in controlling the number of rib-bearing vertebra and positioning of the sacrum. Independent of this, 196a1, 196a2, and 196b act redundantly to constrain total vertebral number. Loss of miR-196 leads to a collective up-regulation of numerous trunk Hox target genes with a concomitant delay in activation of caudal Hox genes, which are proposed to signal the end of axis extension. Additionally, we identified altered molecular signatures associated with the Wnt, Fgf, and Notch/segmentation pathways and demonstrate that miR-196 has the potential to regulate Wnt activity by multiple mechanisms. By feeding into, and thereby integrating, multiple genetic networks controlling vertebral number and identity, miR-196 is a critical player defining axial formulae.

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Interaction of Wnt3a, Msgn1 and Tbx6 in neural versus paraxial mesoderm lineage commitment and paraxial mesoderm differentiation in the mouse embryo

Cited by 80 publications

References 31 publications

Wnt5aandWnt11regulate mammalian anterior-posterior axis elongation

Wnt5aandWnt11regulate mammalian anterior-posterior axis elongation

Wnt signaling andtbx16form a bistable switch to commit bipotential progenitors to mesoderm

Independent regulation of vertebral number and vertebral identity by microRNA-196 paralogs

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