Simulation of the nodal flow of mutant embryos with a small number of cilia: comparison of mechanosensing and vesicle transport hypotheses

Abstract

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/ncomms162410.1038/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 μN m−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.

The cilium as a force sensor−myth versus reality

“…The membrane tension on a cilium is more difficult to estimate. A recent computational result, assuming an elastic membrane, estimates that a shear rate of _ g ¼ 1s À1 leads to a membrane tension of 1 μN/m (Omori et al, 2018). However, this result only holds for short time scales (sub-second).…”

“…A different concept has been proposed for nodal cilia; it involves a stretch-sensitive channel in the membrane of a cilium (Omori et al, 2018) (Fig. 2E).…”

New insights into ion channel‐dependent signalling during left‐right patterning

“…The existence of NVP is highly controversial and mathematical modelling suggests that the flow rates within the node may not be sufficient to transport vesicles (Omori et al . ). An alternative explanation for the chemo‐sensor hypothesis may be the secretion of yet‐unidentified lipidated morphogens within the node.…”

“…Omori et al . () recently modelled the ciliary membrane tension generated by cilia bending in response to nodal flow. According to their models, nodal flow generates a membrane tension at the ciliary base of ∼0.1 μN/m.…”

Simulations of particle tracking in the oligociliated mouse node and implications for left-right symmetry breaking mechanics

“…In section 3.3 an alternative release hypothesis that particles are released directly from the cilium themselves is considered. Particle locations are updated following equation (4), and tracked for 10, 000 beats or (as initialised by [26]) until they reach a height of 0.1 cilium lengths above the nodal floor, when they are considered deposited. The computational cost of the simulations contained within this manuscript was just over 3200 cpu hours.…”