Cell competition corrects noisy Wnt morphogen gradients to achieve robust patterning in the zebrafish embryo

Yuki Akieda,Nobuyuki Shimizu,Shohei Ogamino,Ryutaro Akiyoshi,Takamasa Masuda,Tohru Ishitani,Jumpei Nogami,Shizuka Ishitani,Yasuyuki Ohkawa,Hironobu Furuie

doi:10.1038/s41467-019-12609-4

Yuki Akieda, Nobuyuki Shimizu + Show 8 more

Open Access

https://doi.org/10.1038/s41467-019-12609-4

Copy DOI

Abstract

Morphogen signalling forms an activity gradient and instructs cell identities in a signalling strength-dependent manner to pattern developing tissues. However, developing tissues also undergo dynamic morphogenesis, which may produce cells with unfit morphogen signalling and consequent noisy morphogen gradients. Here we show that a cell competition-related system corrects such noisy morphogen gradients. Zebrafish imaging analyses of the Wnt/β-catenin signalling gradient, which acts as a morphogen to establish embryonic anterior-posterior patterning, identify that unfit cells with abnormal Wnt/β-catenin activity spontaneously appear and produce noise in the gradient. Communication between unfit and neighbouring fit cells via cadherin proteins stimulates apoptosis of the unfit cells by activating Smad signalling and reactive oxygen species production. This unfit cell elimination is required for proper Wnt/β-catenin gradient formation and consequent anterior-posterior patterning. Because this gradient controls patterning not only in the embryo but also in adult tissues, this system may support tissue robustness and disease prevention.

Highlights

Morphogen signalling forms an activity gradient and instructs cell identities in a signalling strength-dependent manner to pattern developing tissues
In some unfit Wnt/β-catenin activity-abnormal cells, caspase-3 was activated (Fig. 1b, right; Supplementary Fig. 2f–g), whereas apoptosis inhibition by anti-apoptotic bcl-2 or caspase inhibitor p35 overexpression reduced physiologically occurring apoptosis (Supplementary Fig. 2c–h), enhanced the appearance of unfit cells with abnormally high or low Wnt/β-catenin activity, and severely distorted the Wnt/β-catenin activity gradient (Fig. 1f, Supplementary Fig. 2i–j). These results suggest that apoptotic elimination of unfit cells smoothens the Wnt/β-catenin-gradient
Smad1/5/8 phosphorylation, which is activated in zebrafish presumptive ventral tissue (Supplementary Fig. 5h) to promote dorsoventral axis formation[23], was not detected in Wnt/β-catenin unfit cells (Supplementary Fig. 5i). These results indicate that the unfit cells activate TGF-β-Smad signalling, which is not activated in normal embryonic tissue, but not bone morphogenetic protein (BMP)-Smad signalling, which controls embryonic dorsoventral patterning in parallel with Wnt/ β-catenin signalling

Summary

Introduction

Morphogen signalling forms an activity gradient and instructs cell identities in a signalling strength-dependent manner to pattern developing tissues. Communication between unfit and neighbouring fit cells via cadherin proteins stimulates apoptosis of the unfit cells by activating Smad signalling and reactive oxygen species production This unfit cell elimination is required for proper Wnt/ β-catenin gradient formation and consequent anterior-posterior patterning. Because this gradient controls patterning in the embryo and in adult tissues, this system may support tissue robustness and disease prevention. Rapid cell proliferation and movement in developing tissues may affect morphogen diffusion and signal transduction, thereby producing cells with unfit signalling and consequent noisy morphogen gradients It is not yet completely understood how these noises are overcome to generate robust patterning. We identify a cell competition-related system for correcting the noise in the Wnt/β-catenin morphogen gradient, presenting a previously unidentified physiological role of cell competition and the mechanisms that mediate unfit cell sensing and elimination

Methods

Results

Conclusion