Synthetic mammalian pattern formation driven by differential diffusivity of Nodal and Lefty

Ryoji Sekine, Tatsuo Shibata, Miki Ebisuya

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Aug 08, 2018
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Received: 25th July 18

Pattern formation is fundamental for embryonic development. Although synthetic biologists have created several patterns, a synthetic mammalian reaction-diffusion pattern has yet to be realized. TGF-beta family proteins Nodal and Lefty have been proposed to meet the conditions for reaction-diffusion patterning: Nodal is a short-range activator that enhances the expression of Nodal and Lefty whereas Lefty acts as a long-range inhibitor against Nodal. However, the pattern forming possibility of the Nodal-Lefty signaling has never been directly tested, and the underlying mechanisms of differential diffusivity of Nodal and Lefty remain unclear. Here, through a combination of synthetic biology and theoretical modeling, we show that a reconstituted minimal network of the Nodal-Lefty signaling spontaneously gives rise to a pattern in mammalian cell culture. Surprisingly, extracellular Nodal was confined underneath the cells as small clusters, resulting in a narrow distribution range compared with Lefty. We further found that the finger 1 domain of the Nodal protein is responsible for its short-range distribution. By transplanting the finger 1 domain of Nodal into Lefty, we converted the originally long-range distribution of Lefty to a short-range one, successfully preventing the pattern formation. These results indicate that the differences in the localization and domain structures between Nodal and Lefty, combined with the activator-inhibitor topology, are sufficient for reaction-diffusion pattern formation in mammalian cells.

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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

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