Organized chaos in Kupffer's vesicle: how a heterogeneous structure achieves consistent left-right patterning

Abstract

Successful establishment of left-right asymmetry is crucial to healthy vertebrate development. In many species this process is initiated in a ciliated, enclosed cavity, for example Kupffer's vesicle (KV) in zebrafish. The microarchitecture of KV is more complex than that present in the left-right organizer of many other species. While swirling flow in KV is recognized as essential for left-right patterning, its generation, nature and conversion to asymmetric gene expression are only beginning to be fully understood. We recently [Sampaio, P et al. Dev Cell 29:716-728] combined imaging, genetics and fluid dynamics simulation to characterize normal and perturbed ciliary activity, and their correlation to asymmetric charon expression and embryonic organ fate. Randomness in cilia number and length have major implications for robust flow generation; even a modest change in mean cilia length has a major effect on flow speed to due to nonlinear scaling arising from fluid mechanics. Wildtype, and mutant embryos with normal liver laterality, exhibit stronger flow on the left prior to asymmetric inhibition of charon. Our discovery of immotile cilia, taken with data on morphant embryos with very few cilia, further support the role of mechanosensing in initiating and/or enhancing flow conversion into gene expression.