Abstract
The systematic breaking of left–right body symmetry is a familiar feature of human physiology. In humans and many animals, this process originates with asymmetric fluid flow driven by rotating cilia, occurring in a short-lived embryonic organizing structure termed the node. The very low–Reynolds number fluid mechanics of this system is reviewed; important features include how cilia rotation combines with tilt to produce asymmetric flow, boundary effects, time dependence, and the interpretation of particle tracking experiments. The effect of perturbing cilia length and number is discussed and compared in mouse and zebrafish. Whereas understanding of this process has advanced significantly over the past two decades, there is still no consensus on how flow is converted to asymmetric gene expression, with most research focusing on resolving mechanical versus morphogen sensing. The underlying process may be more subtle, probably involving a combination of these effects, with fluid mechanics playing a central role.
Highlights
The systematic left–right asymmetry of the interior of the human body is familiar to all of us; unless an individual has the rare condition situs inversus, the heartbeat is clearly palpable on the left side of the chest (Figure 1a)
For example, Siewert and Kartagener’s work on the triad syndrome in the early twentieth century, the discovery of the inversus viscerum (iv/iv) mouse (Hummel & Chapman 1959), the postulate that motile embryonic cilia are instrumental in determining situs (Afzelius 1976), the puzzle regarding motility of iv/iv cilia (Handel & Kennedy 1984), the study of the ventral node of mouse and the discovery of motile cilia (Sulik et al 1994), further debate over the motility of nodal cilia (Supp et al 1997), and the final confirmation of the necessary (Nonaka et al 1998) and sufficient (Nonaka et al 2002) role of cilia-driven flow in determining situs
Through imaging of live cells from a transgenic mouse model expressing a ratiometric genetically encoded calcium indicator, Delling et al (2016) reported that nodal cilia are not calcium-sensitive sensors. These experimental observations, combined with further imaging and modeling of the fluid mechanics of the organizing structures that we review in detail below, have revealed hitherto unexpected subtlety in the process of left–right symmetry breaking
Summary
The systematic left–right asymmetry of the interior of the human body is familiar to all of us; unless an individual has the rare condition situs inversus, the heartbeat is clearly palpable on the left side of the chest (Figure 1a). As is well established in developmental biology, the answer lies with cilia-driven fluid flow taking place early in development This flow is the first left–right asymmetric event and occurs in a short-lived embryonic cavity or organizing structure such as the primitive node in humans (Schoenwolf et al 2014), ventral node of mouse (Figure 1b) (Nonaka et al 1998) and rabbit (Okada et al 2005), and Kupffer’s vesicle (KV) of medakafish (Okada et al 2005) and zebrafish (Essner et al 2005, Kramer-Zucker et al 2005) [the story in the chick embryo is different (see Levin et al 1995, Gros et al 2009)]. Through imaging of live cells from a transgenic mouse model expressing a ratiometric genetically encoded calcium indicator, Delling et al (2016) reported that nodal cilia are not calcium-sensitive sensors These experimental observations, combined with further imaging and modeling of the fluid mechanics of the organizing structures that we review in detail below, have revealed hitherto unexpected subtlety in the process of left–right symmetry breaking. Details of the molecular biology of the left–right pathway are beyond the scope of this article except where they directly affect mechanical parameters such as cilia length and motility; the reader is referred to recent reviews by Shinohara & Hamada (2017) and Schweickert et al (2018)
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