Toshihiro Omori, Katja Winter, Kyosuke Shinohara, Hiroshi Hamada, Takuji Ishikawa

• Left-right (L-R) asymmetry in the body plan is determined by nodal flow in vertebrate embryos. Shinohara et al. (Shinohara K et al. 2012 Nat. Commun. 3, 622 (doi:10.1038/ncomms1624)) used Dpcd and Rfx3 mutant mouse embryos and showed that only a few cilia were sufficient to achieve L-R asymmetry. However, the mechanism underlying the breaking of symmetry by such weak ciliary flow is unclear. Flow-mediated signals associated with the L-R asymmetric organogenesis have not been clarified, and two different hypotheses-vesicle transport and mechanosensing-are now debated in the research field of developmental biology. In this study, we developed a computational model of the node system reported by Shinohara et al. and examined the feasibilities of the two hypotheses with a small number of cilia. With the small number of rotating cilia, flow was induced locally and global strong flow was not observed in the node. Particles were then effectively transported only when they were close to the cilia, and particle transport was strongly dependentLeft-right (L-R) asymmetry in the body plan is determined by nodal flow in vertebrate embryos. Shinohara et al. (Shinohara K et al. 2012 Nat. Commun. 3, 622 (doi:10.1038/ncomms1624)) used Dpcd and Rfx3 mutant mouse embryos and showed that only a few cilia were sufficient to achieve L-R asymmetry. However, the mechanism underlying the breaking of symmetry by such weak ciliary flow is unclear. Flow-mediated signals associated with the L-R asymmetric organogenesis have not been clarified, and two different hypotheses-vesicle transport and mechanosensing-are now debated in the research field of developmental biology. In this study, we developed a computational model of the node system reported by Shinohara et al. and examined the feasibilities of the two hypotheses with a small number of cilia. With the small number of rotating cilia, flow was induced locally and global strong flow was not observed in the node. Particles were then effectively transported only when they were close to the cilia, and particle transport was strongly dependent on the ciliary positions. Although the maximum wall shear rate was also influenced by ciliary position, the mean wall shear rate at the perinodal wall increased monotonically with the number of cilia. We also investigated the membrane tension of immotile cilia, which is relevant to the regulation of mechanotransduction. The results indicated that tension of about 0.1 mu Nm(-1) was exerted at the base even when the fluid shear rate was applied at about 0.1 s(-1). The area of high tension was also localized at the upstream side, and negative tension appeared at the downstream side. Such localization may be useful to sense the flow direction at the periphery, as time-averaged anticlockwise circulation was induced in the node by rotation of a few cilia. Our numerical results support the mechanosensing hypothesis, and we expect that our study will stimulate further experimental investigations of mechanotransduction in the near future.…