Lefty acts as an essential modulator of Nodal activity during sea urchin oral–aboral axis formation

Duboc, Véronique; Lapraz, François; Besnardeau, Lydia; Lepage, Thierry

doi:10.1016/j.ydbio.2008.04.012

Cited by 90 publications

(119 citation statements)

References 47 publications

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“…Lefty is a divergent member of the Tgfβ family. It is so far found only in chordates and ambulacrarians and in the latter does function in LR asymmetry (9,25). Therefore, it is unlikely that Cer and Lefty are more broadly involved in LR asymmetry across protostomes, and we suggest their incorporations into regulation of LR asymmetry are innovations of chordates and deuterostomes, respectively, with negative feedback providing more nuanced control of Nodal signaling in these lineages.…”

Section: Discussionmentioning

confidence: 78%

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Cerberus–Nodal–Lefty–Pitx signaling cascade controls left – right asymmetry in amphioxus

Liu

Xing

et al. 2017

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

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Many bilaterally symmetrical animals develop genetically programmed left-right asymmetries. In vertebrates, this process is under the control of Nodal signaling, which is restricted to the left side by Nodal antagonists Cerberus and Lefty. Amphioxus, the earliest diverging chordate lineage, has profound left-right asymmetry as a larva. We show that Cerberus, Nodal, Lefty, and their target transcription factor Pitx are sequentially activated in amphioxus embryos. We then address their function by transcription activator-like effector nucleases (TALEN)-based knockout and heat-shock promoter (HSP)-driven overexpression. Knockout of Cerberus leads to ectopic right-sided expression of Nodal, Lefty, and Pitx, whereas overexpression of Cerberus represses their left-sided expression. Overexpression of Nodal in turn represses Cerberus and activates Lefty and Pitx ectopically on the right side. We also show Lefty represses Nodal, whereas Pitx activates Nodal. These data combine in a model in which Cerberus determines whether the left-sided gene expression cassette is activated or repressed. These regulatory steps are essential for normal left-right asymmetry to develop, as when they are disrupted embryos may instead form two phenotypic left sides or two phenotypic right sides. Our study shows the regulatory cassette controlling left-right asymmetry was in place in the ancestor of amphioxus and vertebrates. This includes the Nodal inhibitors Cerberus and Lefty, both of which operate in feedback loops with Nodal and combine to establish asymmetric Pitx expression. Cerberus and Lefty are missing from most invertebrate lineages, marking this mechanism as an innovation in the lineage leading to modern chordates.B ilaterians share three primary developmental axes. The anterior-posterior (AP) and dorsal-ventral (DV) axes define bilaterally symmetrical organization. The third axis, orthogonal to these, is known as the medial-lateral or left-right (LR) axis and displays mirror-image symmetry. However, many bilaterian species deviate consistently from true symmetry, raising fundamental questions of how symmetry is broken and how different developmental programs can unfold on the left and right sides of an organism (1). In vertebrates, this includes asymmetric development of the heart and viscera, disruption of which during embryogenesis causes a range of human disorders (2).Correct LR organization in vertebrates is regulated by a gene cassette in which right-sided Cerberus (Cer) and left-sided Nodal and Lefty regulate left-sided expression of the Pitx family gene Pitx2 and hence morphological LR asymmetry (3). Cer expression on the right of the embryonic node is required to repress Nodal signaling, which happens by Cer protein binding directly to Nodal protein. This restricts the ability of Nodal protein to activate the expression of the Nodal gene, leading to an up-regulation of Nodal on the left of the embryo. Lefty expression is also up-regulated by Nodal and, like Cer, acts as an extracellular inhibitor of Nodal. Coexpression o...

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Section: Discussionmentioning

confidence: 78%

“…In vertebrate embryos, Lefty also acts as an extracellular inhibitor of Nodal protein, and experiments in an echinoderm suggest this might also be the case in this lineage (25). To test the function of Lefty in amphioxus, we generated embryos in which the Lefty gene was targeted by injection of a TALEN mRNA (SI Appendix, Fig.…”

Section: Resultsmentioning

confidence: 99%

Cerberus–Nodal–Lefty–Pitx signaling cascade controls left – right asymmetry in amphioxus

Liu

Xing

et al. 2017

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

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“…Importantly, developmental studies in fishes reveal that epithalamic asymmetry is preceded and controlled by the asymmetric expression of Nodal (figure 1c-e) [20][21][22] (see details below in §4). In echinoderms, Nodal is expressed in the right ciliary band, specifically in a cluster of prospective neurons located on the right side of the apical tuft (figure 1f ) [23]. However, the presence of asymmetry in this neural structure is yet to be determined.…”

Section: Nodal and Nervous System Asymmetry Across Metazoansmentioning

confidence: 99%

Nodal signalling and asymmetry of the nervous system

Signore

Palma

Concha

2016

Phil. Trans. R. Soc. B

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One contribution of 17 to a theme issue 'Provocative questions in left -right asymmetry'. The role of Nodal signalling in nervous system asymmetry is still poorly understood. Here, we review and discuss how asymmetric Nodal signalling controls the ontogeny of nervous system asymmetry using a comparative developmental perspective. A detailed analysis of asymmetry in ascidians and fishes reveals a critical context-dependency of Nodal function and emphasizes that bilaterally paired and midline-unpaired structures/organs behave as different entities. We propose a conceptual framework to dissect the developmental function of Nodal as asymmetry inducer and laterality modulator in the nervous system, which can be used to study other types of body and visceral organ asymmetries. Using insights from developmental biology, we also present novel evolutionary hypotheses on how Nodal led the evolution of directional asymmetry in the brain, with a particular focus on the epithalamus. We intend this paper to provide a synthesis on how Nodal signalling controls left-right asymmetry of the nervous system. This article is part of the themed issue 'Provocative questions in leftright asymmetry'.

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“…Abundant comparative evidence exists for other euechinoid taxa as well, including Lytechinus variegatus (Lv) (31)(32)(33)(34)(35)(36)(37) and Paracentrotus lividus (Pl) (38)(39)(40)(41)(42). Data from these indirectdeveloping euechinoids indicate that although these taxa diverged from one another ∼90 mya (9, 43), very little appreciable change to their developmental GRNs has accrued (44)(45)(46).…”

mentioning

confidence: 99%

Divergence of ectodermal and mesodermal gene regulatory network linkages in early development of sea urchins

Erkenbrack

2016

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

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Developmental gene regulatory networks (GRNs) are assemblages of gene regulatory interactions that direct ontogeny of animal body plans. Studies of GRNs operating in the early development of euechinoid sea urchins have revealed that little appreciable change has occurred since their divergence ∼90 million years ago (mya). These observations suggest that strong conservation of GRN architecture was maintained in early development of the sea urchin lineage. Testing whether this holds for all sea urchins necessitates comparative analyses of echinoid taxa that diverged deeper in geological time. Recent studies highlighted extensive divergence of skeletogenic mesoderm specification in the sister clade of euechinoids, the cidaroids, suggesting that comparative analyses of cidaroid GRN architecture may confer a greater understanding of the evolutionary dynamics of developmental GRNs. Here I report spatiotemporal patterning of 55 regulatory genes and perturbation analyses of key regulatory genes involved in euechinoid oral-aboral patterning of nonskeletogenic mesodermal and ectodermal domains in early development of the cidaroid Eucidaris tribuloides. These results indicate that developmental GRNs directing mesodermal and ectodermal specification have undergone marked alterations since the divergence of cidaroids and euechinoids. Notably, statistical and clustering analyses of echinoid temporal gene expression datasets indicate that regulation of mesodermal genes has diverged more markedly than regulation of ectodermal genes. Although research on indirectdeveloping euechinoid sea urchins suggests strong conservation of GRN circuitry during early embryogenesis, this study indicates that since the divergence of cidaroids and euechinoids, developmental GRNs have undergone significant, cell typebiased alterations.gene regulatory network | echinoderms | sea urchin embryogenesis | embryonic axis specification | echinoids

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Lefty acts as an essential modulator of Nodal activity during sea urchin oral–aboral axis formation

Cited by 90 publications

References 47 publications

Cerberus–Nodal–Lefty–Pitx signaling cascade controls left – right asymmetry in amphioxus

Cerberus–Nodal–Lefty–Pitx signaling cascade controls left – right asymmetry in amphioxus

Nodal signalling and asymmetry of the nervous system

Divergence of ectodermal and mesodermal gene regulatory network linkages in early development of sea urchins

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