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Developmental Biology - Cell Change

Competition Between Cells Exerts Change

New study reveals competition between cells with normal and abnormal Wnt/-catenin creates cell changes...

Tissue patterning is important to the process of embryo formation just as in the formation of adult tissues. It ensures groups of cells are correctly arranged so they can function properly. Much research wants to understand how improper arrangement or poor signaling between cells can be removed from healthy tissue. But, so far none provide a clear explanation for cell failure until now.

Published in Nature Communications, a research team led by experts from Osaka University investigated Wnt/-catenin signaling, which is a morphogen system that helps control tissue organization in developing embryos across species.

The species included are amphioxi, fish, frogs, and mammals. Using a zebrafish model, researchers found that untypical Wnt/-catenin signaling led to changes in membrane function and levels of proteins produce. These changes were indicators of poor cell fitness and led to cell death, which encouraged consistent tissue patterning during embryo formation.
"We found that a type of 'morphogen-gradient noise-cancelling system' senses and eliminates unhealthy cells, which are accidentally generated during embryogenesis. Our findings suggest that this system is essential for the construction of a healthy embryo with appropriate tissue patterning."

Tohru Ishitani PhD, Laboratory of Integrated Signaling Systems, Department of Molecular Medicine, Institute for Molecular & Cellular Regulation, Gunma University, Gunma, Japan; Department of Homeostatic Regulation, Division of Cellular and Molecular Biology, Research Institute for Microbial Diseases, Osaka University, Japan; Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan and corresponding author on the study.

In the study, cells with aberrant Wnt/-catenin signaling also demonstrated changes in cadherin proteins on the cell membrane, which led to an imbalance relative to cadherin proteins on neighboring cells. In those same cells with aberrant Wnt/-catenin signaling, the activation of TGF--Smad signaling led to the production of reactive oxygen species, followed by cell death via apoptosis.
"Our analyses revealed that this 'morphogen-gradient noise-cancelling system' is only activated in cells with dramatic changes in Wnt/-catenin signaling, or substantial noise. We presume that this system might help to eliminate cells with severe signaling-defects related to malformation- or cancer-causing mutations."

Yuki Akieda PhD, Laboratory of Integrated Signaling Systems, Department of Molecular Medicine, Institute for Molecular & Cellular Regulation, Gunma University, Japan; Department of Homeostatic Regulation, Division of Cellular and Molecular Biology, Research Institute for Microbial Diseases, Osaka University, Japan and lead author.

Because of the importance of ensuring appropriate tissue patterning, the results of this study can help to explain mechanisms involved in the formation of cancer and the occurrence of congenital diseases. In addition, the results may be useful for designing new diagnostic methods for these diseases.

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/-catenin signalling gradient, which acts as a morphogen to establish embryonic anterior-posterior patterning, identify that unfit cells with abnormal Wnt/-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/-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.

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

The authors thank A. Kikuchi, E. Raz, A. Nagafuchi, M. Hibi, G. Salvesen, E. Fisher, W. El-Deiry, Y. Fujita, A. Yoshimura, S. Korsmeyer, M. Okada, and K. Kawakami for providing the plasmids; ZIRC and NBRP for providing transgenic zebrafish; A. Nagafuchi for helpful discussion; the Advanced Computational Scientific Program of the Research Institute for Information Technology, Kyushu University, Y. Sato in Nagoya University Live Imaging Center, Y. Kamei and T. Yabe in NIBB, J. Konno and Y. Kamihara in Olympus, NBRP zebrafish, and Ishitani lab members (Y. Sado, H. Okumura, M. Matsuo, M. Sakuma, K. Taniguchi, Y. Haraoka, M. Oginuma, and C. Mogi) for their technical support and fish maintenance. This research was supported by the Sumitomo Foundation and Takeda Foundation (T.I.), the Cooperative Research Project Program of MIB, Kyushu University (T.I. and Y.O.), AMED (JP18gm5010001) (T.I.), JSPS Research Fellowships for Young Scientists (Y.A.), JST CREST (JPMJCR16G1) (Y.O.), and a Grant-in-Aid for Scientific Research on Innovative Areas (25117720) (T.I.) (25116010, 18H04802, 18H05527, 19H05244) (Y.O.), Young Scientists (24790286,17K17942) (S.I.) (20770514) (Y.A.), and Scientific Research (B) (16H05141, 19H03412) (T.I.).

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Oct 28 2019   Fetal Timeline   Maternal Timeline   News  

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The 'morphogen-gradient noise-cancelling system' senses and eliminates unhealthy cells
that are accidentally generated during embryogenesis. This system is essential for
the construction of a healthy embryo body. CREDIT Osaka University.

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