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

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.

Axis Specification in Zebrafish Is Robust to Cell Mixing and Reveals a Regulation of Pattern Formation by Morphogenesis

“…Primary antibodies used were as follows – anti phosophoSmad2/3 (8828, Cell Signaling Technologies); anti-ppERK (M9692-200UL, Sigma); anti beta-catenin (C7207, Sigma). Antibodies validated against targets: anti phosophoSmad2/3 – [ 45 ]; anti-ppERK [ 46 ]; anti beta-catenin [ 47 ].…”

Optogenetic investigation of BMP target gene expression diversity

“…The gradient threshold model proposes that gene-specific activation thresholds are responsible for differences in the spatial expression of target genes ( Sharpe, 2019 ; Briscoe and Small, 2015 ; Dubrulle et al, 2015 ; Rogers and Schier, 2011 ; Barkai and Shilo, 2009 ; Ashe and Briscoe, 2006 ). Can gradients be reliably generated and signaling thresholds accurately interpreted with high sensitivity, or do gradients simply provide a ‘rough framework’ for patterning that is refined over time by other mechanisms such as target gene cross-talk ( Briscoe and Small, 2015 ; Chen et al, 2012 ) or cell sorting ( Akieda et al, 2019 ; Xiong et al, 2013 )? In the former case, is such precision actually required for patterning?…”

“…Together with previous work (reviewed in Zinski et al, 2018 ), several of our observations indicate that feedback is an important feature of the BMP patterning system: Five out of 16 high-confidence BMP target genes affect BMP signaling ( Figure 1—figure supplement 1 ), and embryos can experience a dip in signaling levels after a signaling pulse ( Figure 3C and Figure 3—figure supplement 1J ). Cell sorting strategies that sharpen gene expression boundaries may also contribute to the observed recovery from BMP signaling manipulation ( Akieda et al, 2019 ; Xiong et al, 2013 ).…”

Modeling of Wnt-mediated tissue patterning in vertebrate embryogenesis

“…If individual cells are located within a region with which they do not share the same fate and several rows away from the boundary zone, the local nature of contact-mediated cell-cell interactions cannot provide sufficient information to guide cells to the correct compartment. In several developmental contexts, apoptosis has been suggested to play an essential role in tissue remodeling during development [53,54]. Indeed, cells with a strongly different Wnt/β-catenin activity compared to their neighbor cells undergo apoptosis by activating Smad signalling and reactive oxygen species.…”