Editors' ChoiceDevelopmental Biology

Pkd2 Knows the Flow

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Science Signaling  16 Oct 2012:
Vol. 5, Issue 246, pp. ec270
DOI: 10.1126/scisignal.2003689

Left-right (LR) asymmetry in developing vertebrate embryos arises from leftward fluid flow in the node, a ventral structure composed of ciliated pit and crown cells. The motile cilia of pit cells generate the fluid flow and are surrounded by crown cells bearing mostly nonmotile cilia. It is not clear whether this asymmetric flow is sensed directly by mechanosensation or concentrates a chemical factor on the left, but the result is asymmetric expression of genes encoding the patterning proteins Nodal, Paired-like homeodomain transcription factor 2 (Pitx2), and Cerberus-like 2 (Cerl2), with Nodal and Pitx2 enriched on the left and Cerl2 enriched on the right side. Yoshiba et al. report that the calcium channel Polycystin-2 (Pkd2), which is associated with human polycystic kidney disease and cilia function, is required for sensing fluid flow in the mouse node. Pkd2 was expressed ubiquitously in early mouse embryos, and Pkd2–/– embryos showed typical LR patterning defects, including symmetric expression of Nodal and Cerl2 in the crown cells. Restoring Pkd2 in the entire node or in only the crown cells rescued LR patterning, but restoring Pkd2 in only the pit cells did not. Pkd2 localized to cilia in the crown cells, where it was required for LR patterning and for right-enriched Cerl2 expression in these cells. Genetic interaction experiments indicated that Cerl2, not Nodal, expression was affected by Pkd2-mediated signaling. Embryos lacking the intraflagellar transport protein Kif3a lack cilia in all node cells and exhibit LR patterning defects, but restoring Kif3a specifically in crown cells rescued asymmetric gene expression and restored a weak leftward flow, likely due to the presence of a few motile cilia in crown cells. When these embryos that had cilia only in the crown cells were subjected to an experimentally imposed reversed (rightward) fluid flow, Pitx2 expression was also reversed. These results suggest a model in which the immotile cilia of crown cells sense fluid flow in the node to initiate Pkd2-dependent signaling that results in the asymmetric expression of patterning genes. Surprisingly, Ca2+ imaging revealed that Ca2+ signals in the crown cells were symmetrical. The implications of this finding and potential mechanisms for how Pkd2 senses fluid flow are discussed in a Perspective by Norris and Grimes.

S. Yoshiba, H. Shiratori, I. Y. Kuo, A. Kawasumi, K. Shinohara, S. Nonaka, Y. Asai, G. Sasaki, J. A. Belo, H. Sasaki, J. Nakai, B. Dworniczak, B. E. Ehrlich, P. Pennekamp, H. Hamada, Cilia at the node of mouse embryos sense fluid flow for left-right determination via Pkd2. Science 338, 226–231 (2012). [Abstract] [Full Text]

D. P. Norris, D. T. Grimes, Cilia discern left from right. Science 338, 206–207 (2012). [Abstract] [Full Text]

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