Chemosignalling, mechanotransduction and ciliary behaviour in the embryonic node: Computational evaluation of competing theories

Precise specification of left-right asymmetry is essential for patterning the internal organs of vertebrates. Within the embryonic node, posteriorly polarised cilia rotate, causing a leftward fluid flow (nodal flow) that establishes left-right asymmetry. The mechanism by which an embryo senses nodal flow remains uncertain. Existing hypotheses argue that either nodal flow carries morphogen(s) or lipid-bounded vesicles towards the left, thereby generating an asymmetric signal, and/or that mechano-sensory cilia sense this unidirectional flow, stimulating left-sided intracellular calcium signalling. To date, direct and definitive evidence supporting these hypotheses has been lacking. In this study, we conduct a multiscale study to simulate the nodal cilia and the fluidic environment, analysing left-right signal transmission. By employing computational simulation techniques and solving the relevant three-dimensional unsteady transport equations, we study the flow pattern produced by the rotation of active cilia. By importing dilute species and particles into the computational domain, we investigate the transport of morphogens and nodal vesicular parcels, respectively. Furthermore, by extending the analysis to include the solid mechanics of passive deformable cilia and the coupling of their structural behaviour with the emerging fluid mechanics, we study the response of passive cilia to the nodal flow. Our results reproduce the unidirectional nodal flow, allowing us to evaluate the plausibility of both chemo- and mechano-sensing hypotheses. The quantitative measurements of the flow rate, the molecular transport and distribution provide guidance regarding the necessary morphogen molecular weights to break signalling symmetry. The passive sensory ciliary deformation gives indications regarding the plausibility of this mechano-signalling mechanism.