A unified model for left–right asymmetry? Comparison and synthesis of molecular models of embryonic laterality

Vandenberg, Laura N.; Levin, Michael

doi:10.1016/j.ydbio.2013.03.021

Cited by 148 publications

(185 citation statements)

References 199 publications

(280 reference statements)

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“…Around E8.5, when the linear heart tube begins elongating as a result of deployment of SHF cells, it undergoes a rightward spiral looping under the influence of the left -right asymmetry Cohen et al 2008. ) genetic network (Vandenberg and Levin 2013), and this looped form creates the prepattern for further remodeling (Fig. 2C).…”

Section: Heart Developmentmentioning

confidence: 99%

Genetic Networks Governing Heart Development

Waardenberg

Ramialison

Bouveret

et al. 2014

Cold Spring Harbor Perspectives in Medicine

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Animal genomes contain a code for construction of the body plan from a fertilized egg. Understanding how genome information is deciphered to create the complex multilayered regulatory systems that drive organismal development, and which become altered in disease, is one of the greatest challenges in the biological sciences. The development of methods that effectively represent and communicate the complexity inherent in gene regulatory networks remains a major barrier. This review introduces the philosophy of systems biology and discusses recent progress in understanding the development of the heart at a systems biology level. SYSTEMS BIOLOGYS ystems biology is an emerging multidisciplinary field embedded in large-scale data initiatives that seeks to understand the complex interactions occurring within biological systems. The recent increase in popularity of systems biology has been the consequence of technological advances that have flowed from the sequencing of the human genome (Lander et al. 2001). However, the last decade of research has reinforced the notion that to understand biological networks we need to do more than just describe genome organization. A major finding that has reshaped our view of biology is the realization that transcriptional complexity rather than genome size or the number of protein-coding genes is the evolutionary driver for increased biological diversity (Britten and Davidson 1969;Carninci et al. 2005;Fantom Consortium et al. 2014).Network theory hypothesizes that specific interaction patterns in biology have logic and functional significance. The discovery that uni-

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Section: Heart Developmentmentioning

confidence: 99%

Genetic Networks Governing Heart Development

Waardenberg

Ramialison

Bouveret

et al. 2014

Cold Spring Harbor Perspectives in Medicine

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“…Much has been written about the diversity of developmental routes to leftright asymmetry in animals ( [7][8][9][10] and references therein) and plants [11][12][13]. One common theme emerges from studies of molecular mechanisms: asymmetry at the macroscopic level can often be traced back to subcellular (e.g.…”

Section: Introduction: Direction Of Asymmetry (A) Backgroundmentioning

confidence: 99%

What determines direction of asymmetry: genes, environment or chance?

Palmer¹

2016

Phil. Trans. R. Soc. B

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One contribution of 17 to a theme issue 'Provocative questions in left -right asymmetry'. Conspicuous asymmetries seen in many animals and plants offer diverse opportunities to test how the development of a similar morphological feature has evolved in wildly different types of organisms. One key question is: do common rules govern how direction of asymmetry is determined (symmetry is broken) during ontogeny to yield an asymmetrical individual? Examples from numerous organisms illustrate how diverse this process is. These examples also provide some surprising answers to related questions. Is direction of asymmetry in an individual determined by genes, environment or chance? Is direction of asymmetry determined locally (structure by structure) or globally (at the level of the whole body)? Does direction of asymmetry persist when an asymmetrical structure regenerates following autotomy? The answers vary greatly for asymmetries as diverse as gastropod coiling direction, flatfish eye side, crossbill finch bill crossing, asymmetrical claws in shrimp, lobsters and crabs, katydid sound-producing structures, earwig penises and various plant asymmetries. Several examples also reveal how stochastic asymmetry in mollusc and crustacean early cleavage, in Drosophila oogenesis, and in Caenorhabditis elegans epidermal blast cell movement, is a normal component of deterministic development. Collectively, these examples shed light on the role of genes as leaders or followers in evolution.This article is part of the themed issue 'Provocative questions in leftright asymmetry'.

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“…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.…”

mentioning

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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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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A unified model for left–right asymmetry? Comparison and synthesis of molecular models of embryonic laterality

Cited by 148 publications

References 199 publications

Genetic Networks Governing Heart Development

Genetic Networks Governing Heart Development

What determines direction of asymmetry: genes, environment or chance?

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

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