Immotile cilia mechanically sense the direction of fluid flow for left-right determination

Abstract

Immotile cilia at the ventral node of mouse embryos are required for sensing leftward fluid flow that breaks left-right symmetry of the body. However, the flow-sensing mechanism has long remained elusive. In this work, we show that immotile cilia at the node undergo asymmetric deformation along the dorsoventral axis in response to the flow. Application of mechanical stimuli to immotile cilia by optical tweezers induced calcium ion transients and degradation of Dand5 messenger RNA (mRNA) in the targeted cells. The Pkd2 channel protein was preferentially localized to the dorsal side of immotile cilia, and calcium ion transients were preferentially induced by mechanical stimuli directed toward the ventral side. Our results uncover the biophysical mechanism by which immotile cilia at the node sense the direction of fluid flow.

Leftward transfer of a chemosensory polycystin initiates left-dominant calcium signaling for lateralized embryonic development

“…This would be feasible because many PKD channels have been reported to serve for chemical sensing of the peptides, morphogens, and tastes (Ha et al ., 2020; Horio et al ., 2011; Kim et al ., 2016). However, this argument is neutral from the long-lasting debate whether PKD channels in the ventral node can serve for mechanosensation of the fluid flow (Delling et al ., 2016; Djenoune et al ., 2023; Katoh et al ., 2023; Yoshiba et al ., 2012), because it is also likely that any mechanical stress on nodal cilia can potentiate the chemosensory properties of PKD channels. Although the Nodal mRNA in the ECCs has been reported to gradually lateralized to the left during the 4–5 somite stages (Mizuno et al ., 2020), which may follow the stage of initial [Ca 2+ ] i elevation ( Fig.…”

“…Cilia are generally involved in chemosensory function in many organisms (Pazour and Witman, 2003;Signor et al, 1999;Singla and Reiter, 2006), and some cilia can also secrete PKD-containing extracellular vesicles (EVs) to facilitate its long-range transfer (Wang et al, 2021;Wood and Rosenbaum, 2015). The "two-cilia theory" that these polycystins may serve as a mechanosensor for cilia bending (Djenoune et al, 2023;Katoh et al, 2023;Tabin and Vogan, 2003;Yoshiba et al, 2012) has however been challenged by the preprint (which was not certified by peer review) is the author/funder. All rights reserved.…”

“…Cilia are generally involved in chemosensory function in many organisms (Pazour and Witman, 2003; Signor et al, 1999; Singla and Reiter, 2006), and some cilia can also secrete PKD-containing extracellular vesicles (EVs) to facilitate its long-range transfer (Wang et al, 2021; Wood and Rosenbaum, 2015). The “two-cilia theory” that these polycystins may serve as a mechanosensor for cilia bending (Djenoune et al, 2023; Katoh et al, 2023; McGrath and Brueckner, 2003; Tabin and Vogan, 2003; Yoshiba et al, 2012) has however been challenged by the experimental evidence for that an artificial fluid flow does not apparently bend the cilia or elevate the intraciliary calcium (Delling et al, 2016; Tajhya and Delling, 2020). In addition, chemosensory properties of the PKD1/2 channels have been identified in other systems (Ha et al, 2020; Horio et al, 2011; Kim et al, 2016).…”

Functions of cilia in cardiac development and disease

“…The mechanosensory role of primary cilia in heart development Primary cilia are known to have a role as fluid shear stress sensor at node (McGrath et al, 2003) and in the kidney (Nauli et al, 2006;Xu et al, 2007Xu et al, , 2009; however, the exact mechanism by which biomechanical forces regulate gene expression is not fully understood. Yet, the mechanosensory function of primary cilia during development cannot be ignored (Djenoune et al, 2023;Katoh et al, 2023). Extensive tissue remodeling during heart development dramatically changes cardiac fluid shear stress patterns (Garoffolo & Pesce, 2019).…”

Inverse blebs operate as hydraulic pumps during mouse blastocyst formation

“…In some of the most striking relocations of IF, pressurized fluid can even fracture tissues 3,13,14 . In large fluid compartments, such as lumens, the movement of IF can be controlled by specialized cell protrusions called cilia 15 , but in packed tissues we are only beginning to understand how cells control the fluid surrounding them 16 .…”