Differential Diffusivity of Nodal and Lefty Underlies a Reaction-Diffusion Patterning System

Müller, Patrick; Rogers, Katherine W.; Jordan, Ben M.; Lee, Joon S.; Robson, Drew N.; Ramanathan, Sharad; Schier, Alexander F.

doi:10.1126/science.1221920

Cited by 358 publications

(489 citation statements)

References 102 publications

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“…In biology, where networks of cells arise naturally, the Turing model remains controversial because comparison of experiment and theory is hampered by incomplete knowledge of the morphogens involved in development, the rate constants of the reactions, the mechanisms of intercellular coupling, and the role of elasticity (5,7,15,16).…”

mentioning

confidence: 99%

Testing Turing’s theory of morphogenesis in chemical cells

Tompkins¹,

Li²,

Girabawe³

et al. 2014

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

182

172

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Significance Turing proposed that intercellular reaction-diffusion of molecules is responsible for morphogenesis. The impact of this paradigm has been profound. We exploit an abiological experimental system of emulsion drops containing the Belousov–Zhabotinsky reactants ideally suited to test Turing’s theory. Our experiments verify Turing’s thesis of the chemical basis of morphogenesis and reveal a pattern, not previously predicted by theory, which we explain by extending Turing’s model to include heterogeneity. Quantitative experimental results obtained using this artificial cellular system establish the strengths and weaknesses of the Turing model, applicable to biology and materials science alike, and pinpoint which directions are required for improvement.

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mentioning

confidence: 99%

Testing Turing’s theory of morphogenesis in chemical cells

Tompkins¹,

Li²,

Girabawe³

et al. 2014

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

182

172

View full text Add to dashboard Cite

show abstract

“…cDNAs into living embryos (Sanders et al, 2013;Toyoda et al, 2010), by injection of in vitro-synthesized mRNAs into embryos (Muller et al, 2012), and from transgenes under heterologous regulation such as the Gal4-UAS system (Callejo et al, 2011;Kicheva et al, 2007;Zhou et al, 2012). Protein dispersing from expressing cells has been detected by fluorescent imaging, but because expression at an ectopic site can have unforeseen consequences if the systems that normally process and release the morphogen are overwhelmed, or if subcellular structures that are involved are influenced by expression levels, even these direct measures can be problematic in contexts of overexpression and abnormal regulation.…”

Section: Direct Imaging Of Functional Hh Proteinmentioning

confidence: 99%

Essential basal cytonemes take up Hedgehog in the Drosophila wing imaginal disc

et al. 2017

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Morphogen concentration gradients that extend across developmental fields form by dispersion from source cells. In the Drosophila wing disc, Hedgehog (Hh) produced by posterior compartment cells distributes in a concentration gradient to adjacent cells of the anterior compartment. We monitored Hh:GFP after pulsed expression, and analyzed the movement and colocalization of Hh, Patched (Ptc) and Smoothened (Smo) proteins tagged with GFP or mCherry and expressed at physiological levels from bacterial artificial chromosome transgenes. Hh:GFP moved to basal subcellular locations prior to release from posterior compartment cells that express it, and was taken up by basal cytonemes that extend to the source cells. Hh and Ptc were present in puncta that moved along the basal cytonemes and formed characteristic apical-basal distributions in the anterior compartment cells. The basal cytonemes required diaphanous, SCAR, Neuroglian and Synaptobrevin, and both the Hh gradient and Hh signaling declined under conditions in which the cytonemes were compromised. These findings show that in the wing disc, Hh distributions and signaling are dependent upon basal release and uptake, and on cytoneme-mediated movement. No evidence for apical dispersion was obtained.

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“…Lefty expression is also up-regulated by Nodal and, like Cer, acts as an extracellular inhibitor of Nodal. Coexpression of Nodal and Lefty can act as an activator-inhibitor system in the sense originally described by Turing (4). Nodal on the left of the embryo activates expression of Pitx2, which directs the development of left-sided morphology (3).…”

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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Differential Diffusivity of Nodal and Lefty Underlies a Reaction-Diffusion Patterning System

Cited by 358 publications

References 102 publications

Testing Turing’s theory of morphogenesis in chemical cells

Testing Turing’s theory of morphogenesis in chemical cells

Essential basal cytonemes take up Hedgehog in the Drosophila wing imaginal disc

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

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