The internal organs of all vertebrates show distinct left-right (L-R) asymmetry. The earliest known event in the establishment of this asymmetry is a leftwards extracellular fluid flow at the embryonic node. This ‘nodal flow’, which is generated by the rotational movement of node cilia, activates asymmetric gene expression. But how is nodal flow detected? The two-cilia hypothesis proposes that, whereas motile cilia generate the flow, immobile node cilia detect nodal flow and respond by generating a left-sided Ca2+ signal. This signal generation is thought to be mediated by a complex consisting of the calcium channel polycystic kidney disease 2 (Pkd2) and an unknown sensor protein. In this issue, two papers further evaluate this hypothesis.
On p. 1131, Dominic Norris and colleagues identify the Pkd1-related locus Pkd1l1 as the missing Pkd2 partner and sensor protein in L-R patterning in mouse. Point mutants in either Pkd1l1 or Pkd2 fail to activate asymmetric gene expression at the node, they report, and develop similar L-R patterning defects. Cilia and node morphology and cilia motility are normal in both types of mutant, however, which suggests that Pkd1l1 and Pkd2 act downstream of nodal flow. Moreover, Pkd1l1 and Pkd2 localise to cilia and interact physically. Thus, the researchers propose, Pkd1l1 and Pkd2 form a cilia-specific stress-responsive channel in the node, a conclusion consistent with the two-cilia hypothesis.
On p. 1121, Hiroyuki Takeda and colleagues report that the medaka mutant abecobe is defective for L-R asymmetric gene expression but not for nodal flow, and identify the abecobe gene as Pkd1l1. They show that Pkd1l1 expression is confined to Kuppfer's vesicle (KV; a medaka organ equivalent to the mouse node) and that, as in the mouse, Pkd1l1 interacts with and colocalises with Pkd2 in KV cilia. However, importantly, the researchers report that all KV cilia contain Pkd1l1 and Pkd2 and that all of the KV cilia are motile. These results necessitate reconsideration of the two-cilia model for L-R patterning and the researchers propose a new model in which cilia both generate nodal flow and interpret it through a nodal flow sensor that consists of Pkd1l1-Pkd2 complexes.