Editors' ChoiceDevelopmental Biology

Promoting Ciliogenesis with a Prostaglandin

Science Signaling  09 Sep 2014:
Vol. 7, Issue 342, pp. ec244
DOI: 10.1126/scisignal.2005878

Primary cilia are organelles involved in the transduction of extracellular stimuli. Cyclic AMP (cAMP) signaling speeds up anterograde intraflagellar transport in cilia, which increases cilium length, and a natural ligand that can trigger the generation of cAMP is prostaglandin E2 (PGE2), which activates the EP4 receptor. Abnormalities in the formation of cilia are linked to various developmental and organogenesis defects. Jin et al. (see also Barbry and Zaragosi) performed a zebrafish genetic screen and found that leakytail (lkt) mutants had short or no cilia in various ciliated organs, including in the Kupffer’s vesicle, which is a structure necessary for proper early embryonic development. lkt mutants also had multiple phenotypes that occur in zebrafish with defects in cilia formation, such as lack of asymmetric expression of the nodal-related gene southpaw (spaw). The lkt locus encoded a loss-of-function form of ABCC4, the only member of the family of ABCC transporters that transports PGE2. Like human ABCC4, when exogenously expressed in mammalian cells, zebrafish ABCC4 mediated PGE2 export, and application of PGE2 to inner medullary collecting duct 3 (IMCD3) cells accelerated anterograde intraflagellar transport. Cilia on cells in the Kupffer’s vesicle generate a directional fluid flow that establishes left-right patterning during development, and fluid flow in the Kupffer’s vesicle was impaired in lkt mutants or zebrafish embryos injected with morpholino-oligonucleotides (morpholinos) directed against abcc4. Similar to lkt mutants, spaw expression was not asymmetric in abcc4 morphants. Administration of PGE2 to lkt-mutant embryos rescued the cilium-associated phenotypes and partially restored cilium number and length. Embryos injected with morpholinos directed against cox1 or cox2 or both, which encode enzymes necessary for prostaglandin synthesis, showed cilium-related phenotypes to varying degrees of severity, which were partially rescued by application of PGE2. Similarly, embryos injected with morpholinos directed against ep4 showed cilium-related phenotypes, although these defects were partially rescued by application of forskolin, which induces generation of cAMP, but were not rescued by application of PGE2. In human retinal pigment epithelial 1 (hRPE1) cells, transfection of siRNAs directed against ABCC4 or EP4 reduced cilium number and length, defects that were rescued by application of exogenous PGE2 only in cells expressing ABCC4 siRNA. Thus, PGE2 exported by ABCC4 activates EP4 to trigger the generation of cAMP, which stimulates anterograde intraflagellar transport and promotes cilia formation.

D. Jin, T. T. Ni, J. Sun, H. Wan, J. D. Amack, G. Yu, J. Fleming, C. Chiang, W. Li, A. Papierniak, S. Cheepala, G. Conseil, S. P. C. Cole, B. Zhou, I. A. Drummond, J. D. Schuetz, J. Malicki, T. P. Zhong, Prostaglandin signalling regulates ciliogenesis by modulating intraflagellar transport. Nat. Cell Biol. 16, 841–851 (2014). [PubMed]

P. Barbry, L.-E. Zaragosi, An ABC of ciliogenesis. Nat. Cell Biol. 16, 826–827 (2014). [PubMed]