The cilia mechanosensation debate gets (bio)physical

Abstract

For the first time, two new studies applied a mechanical stimulus directly to a cilium, independent of a chemical signal, and demonstrated that force-based bending of a single nodal axoneme is sufficient to induce intraciliary Ca²⁺ flux in a PKD2-dependent manner, which propagated to drive asymmetric gene expression.

Figure 1. Cilia as mechanosensors.

a, Strong genetic and cell biological evidence exists for primary cilia to function in mechanotransduction in the embryonic node in response to nodal flow, and in kidney tubule epithelial cells in response to glomerular flow shear stress. Fluid flow leads to opening of Ca²⁺ ion channels, triggering intraciliary Ca²⁺ transients (1), which initiate intracellular signaling (2), leading to asymmetric gene expression or water resorption, respectively. However, one study concluded that cilia did not function as Ca²⁺-dependent mechanotranducers and that bending under even supraphysiological flow rates was insufficient to trigger intraciliary Ca²⁺ transients. b, Schematic of the mouse left-right organizer LRO (also known as node) showing crown cells with sensory cilia and pit cells with motile cilia, which generate the leftward nodal flow. Bending of cilia in response to nodal flow or force applied directly by optical tweezers is sufficient to trigger intraciliary Ca²⁺ transients (ICOs) (1), promoting intracellular Ca²⁺ signaling (2), which eventually spreads to neighboring cells in the LRO and left mesendoderm (3) to result in asymmetric gene expression^,. This whole program could be initiated after bending a single cilium in immotile cilia mutants and was abolished in loss-of-function Pkd2 mutants. Asymmetric localization of PKD2 (also known as polycystin 2) to clusters enriched along the dorsal side of cilia is proposed to induce a Ca²⁺ response only on the left side of the embryo. c, Open questions remain: (1) Given the forces that are necessary to open mechanosensitive ion channels, is PKD2 directly activated by flow-induced mechanical forces?; (2) Given the lag phase between bending and intraciliary Ca²⁺ transients, is Ca²⁺ the true ‘first’ second messenger or is there another messenger acting upstream, possibly initiating an intracellular Ca²⁺ transient that back-propagates (3)?; (4) How is PKD2 asymmetric localization to the dorsal side of cilia established?