Graduate School of Arts and Sciences, The University of Tokyo

Graduate School of Science, The University of Tokyo

Summary

Assistant Professor Takayoshi Yamamoto, Undergraduate Student Yuta Kambayashi (at the time of the research: 4th Year, College of Arts and Sciences), Graduate Student Yuta Otsuka (at the time of the research: Doctoral Program, Department of Biological Sciences), and Professor Tatsuo Michigami (concurrent appointment, Department of Biological Sciences) of the Graduate School of Arts and Sciences, the University of Tokyo, in collaboration with Professor Stefan Hoppler and colleagues at the University of Aberdeen, UK, They have elucidated the mechanism by which the thin pericardium is formed reproducibly using African clawed frog embryos.

The pericardium is as thin as a water balloon and, together with the pericardial sac fluid, envelopes the heart, absorbing shocks to the heart. The thinness of the pericardium is important for flexible shock absorption, but it was not known how the thin pericardium is formed during the body-building process from the fertilized egg, and how it is always formed at approximately the same thinness without being affected much by various variable factors.

The pericardium forms at high concentrations of the diffusible protein Wnt6, which is produced and secreted by specific cells outside the pericardium and forms a concentration gradient in the cardiac region. When this research group investigated the mechanisms that regulate the amount of Wnt6 receptors, they found that in the cardiac region, the production of Wnt6 receptors is increased in response to the amount of Wnt6 (receptor feedback).

Thus, when Wnt6 is trapped by traps (receptors), it was found that the distribution of Wnt6 is kept within a narrow range by increasing the number of traps to capture more Wnt6. Furthermore, using African clawed frog embryos and mathematical models, we investigated the benefits of this receptor feedback for the organism and found that receptor feedback maintains the thinness of the pericardium despite changes in Wnt production and other factors, allowing for highly reproducible pericardial formation! The results of the study showed that Wnt production is not a major factor.

If Wnt is only kept in a narrow range, a large amount of receptors can be prepared in all cells from the beginning, but it is thought that receptor feedback saves energy for receptor creation, i.e., energy conservation, by creating receptors as needed and where needed.

The research results were published online in the international scientific journal eLife on July 26, 2022 (UK summer time).

Figure: Schematic diagram of the regulation of Wnt distribution during cardiac differentiation process
Wnt6 is secreted from the ectoderm and diffuses extracellularly. In the cardiac mesoderm region, the receptor Frizzled-7 is expressed in response to Wnt6 concentration. The scheduled cardiac muscle region secretes sFRP1, a Wnt-binding inhibitory protein. sFRP1-binding N-acetylated heparan sulfate is expressed in a wide range of scheduled cardiac regions, including the pericardium. These functions narrowly define the pericardial region.

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