Cilia are microtubule-based organelles that mediate signal transduction in a variety of tissues. Despite their importance, the signalling cascades that regulate cilium formation remain incompletely understood. Here we report that prostaglandin signalling affects ciliogenesis by regulating anterograde intraflagellar transport (IFT). Zebrafish leakytail (lkt) mutants show ciliogenesis defects, and the lkt locus encodes an ATP-binding cassette transporter (ABCC4). We show that Lkt/ABCC4 localizes to the cell membrane and exports prostaglandin E2 (PGE2), a function that is abrogated by the Lkt/ABCC4T804M mutant. PGE2 synthesis enzyme cyclooxygenase-1 and its receptor, EP4, which localizes to the cilium and activates the cyclic-AMP-mediated signalling cascade, are required for cilium formation and elongation. Importantly, PGE2 signalling increases anterograde but not retrograde velocity of IFT and promotes ciliogenesis in mammalian cells. These findings lead us to propose that Lkt/ABCC4-mediated PGE2 signalling acts through a ciliary G-protein-coupled receptor, EP4, to upregulate cAMP synthesis and increase anterograde IFT, thereby promoting ciliogenesis.
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We acknowledge P. Yuanyuan and J. Guan for assistance in fish care, X. Zhu for hRPE1 cells, J. Shah for IFT88–EYFP cells, C. Yi for cAMP assays, Q. Li for diagram drawing and L. Cai and G. Zhu for spin-disk confocal microscopy analysis. We are grateful to H. Ma, B. Appel, Z. Sun, J. Gamse and members of our laboratories for comments on the manuscript and helpful discussions. This research was supported in part by grants from the National Basic Research Program of China (CMST2013CB945301, CMST2012CB944501; T.P.Z.), National Natural Science Foundation of China (NSFC31172173; T.P.Z.) and Shanghai Pujiang Program (11PJ1401600; T.P.Z.) as well as the National Institute of Health of America (T.P.Z., J.D.S., J.M., I.A.D.) and Canadian Institutes of Health Research (MOP106513, S.P.C.C.).
The authors declare no competing financial interests.
Integrated supplementary information
(a) cmlc2 expression showing the laterality (left-jagging versus right-jagging) of heart tube in wild-type (wt) embryos and lkt mutants. (b) foxA3 expression depicting the sidedness of liver (black arrow) and pancreas (white arrow) in wt embryos and lkt mutants. (c) insulin expression displaying the pancreas laterality in wt embryos and lkt mutants. (d) lft1 expression showing brain laterality in wt embryos and lkt mutants. (e,f) Acetylated tubulin immunostaining reveals normal pronepheric cilia development in lkt mutants compared with wild-type embryos. Scale bar: 100 μm (a–f); 10 μm (e,f). (g,h) Analysis of sidedness of asymmetric gene expression in wt embryos, lkt mutants and lkt/abcc4 morphant embryos. The total numbers of embryos analysed pooled from n = 3 independent experiments are indicated on the top of each bar. The number of embryos with sided expression of each marker divided by total number of embryos. The percentages of embryos with LR defects were significantly higher in lkt mutants or abcc4 morphants as compared with wt embryos, but not statistically different among lkt mutants or abcc4 morphant embryos (Yates corrected Chi-square test, ∗∗∗P < 0.0001, one degree of freedom). Statistics source data for Supplementary Fig. 1g, h can be found in Supplementary Table 2.
Supplementary Figure 2 Annotated alignment of deduced full-length zebrafish Lkt/ABCC4 protein with orthologs in other species.
Black: identical across four species. Grey: identical in 2 or more species or conservative amino acid substitution. IDs: human (NP005836), mouse (NP001028508), chicken (NP001025990) and zebrafish (EU586042). TM: transmembrane domain. NBD: nucleotide binding domain. Red star: leakytail zebrafish mutation site (T804M). Walker A/B (ATP-binding sites) and signature C are conserved motifs found within the NBD of ABC transporters.
(a) Schematic diagram depicting zebrafish lkt/abcc4 gene structure, including exon 9, 10, 11, and intron 9, 10. Red bar: abcc4 morpholinos target site. Black arrows: primer sites for RT-PCR. (b) RT-PCR analyses showed that wild-type lkt/abcc4 transcripts contained fused exons 9, 10 and 11, whereas mis-spliced transcripts contained only fused exons 9 and 11 in embryos injected with different doses of lkt/abcc4-MO. Total RNAs were isolated from morphants and controls, and subjected to RT-PCR using primers located in exon 9 and 11. (c–e) Acetylated tubulin immunostaining showing a reduction of KV cilia (c), a loss of OV short cilia (d) and lack of some ear kinocilia in lkt/abcc4 morphants (e), similar to those of lkt mutants. (f–h) lkt/abcc4 morphants showing a curved body axis (f; 81%; n = 123), hydrocephalus (f; 78%, n = 123; red arrow), three otoliths (g; 80%; n = 123; red arrows) and reversed (left)-looped heart (h; 41%; n = 93). (i,j) In situ hybridization showing expression of abcc4 (e; arrowhead) and insulin, a pancreas marker (f; arrowhead). (k) Double in situ hybridization with abcc4 and insulin probes showing expression of both genes in the pancreas (arrowhead). Inset displays a high-magnification image of abcc4 and insulin expression patterns, which largely overlap. (l,m) In situ hybridization showing expression of abcc4 (l; arrowhead) and wt1b, a glomerulus marker (m; arrows). (n) Double in situ with abcc4 (arrowhead) and wt1b (arrows) probes showing expression in the pancreas and glomerulus, respectively. Inset shows an enlarged view of abcc4 and wt1b expression. Double in situ hybridization analyses were conducted using digoxingenin-labeled lkt antisense probe (i,k,l,n). insulin (j,k) and wt1b antisense probes (m,n) were fluorescein-labeled. Scale bar: 10 μm (c–e); 100 μm (f–h; i–n).
(a–d) lkt mutants displaying a ventrally curved axis (a), three otoliths (b; red arrows), hydrocephalus (c; red arrow) and reversed (left)-looped heart (d). (e–h) abcc4 mRNA injection rescued mutant phenotypes, including a straight body axis (e), two otoliths (f), normal brain (g) and normal (right)-looped heart (h). Scale bar: 100 μm (a–h). (i) Percentages of rescued lkt mutants grouped in heart looping, otolith biogenesis, axis formation or brain development. Approximately 160 pg of abcc4 mRNA was injected into embryos derived from crosses of lkt heterozygouts. Injected embryos were genotyped using SSLP markers (Z17212 and Z6907). Embryos linking with the lkt mutant genotype but showing wild-type phenotypes were scored as rescued mutants. %: The number of rescued lkt mutants divided by number of all lkt mutants. The total numbers of embryos pooled from n = 3 independent experiments are indicated. Graph shows mean ± s.d.; Student’s t test: ∗∗∗P < 0.001. (j) Bar graph depicting percentages of normal (rescued) brain phenotypes in embryos co-injected with control morpholinos, antisense morpholinos and antisense morpholinos with specific mRNAs. Wild-type embryos were co-injected with cox1-MO (8 ng) with cox1 mRNA (130 pg), cox2-MO (8 ng) with cox2 mRNA (125 pg), ep4-MO (1 ng) with ep4 mRNA (120 pg) or abcc4-MO (12 ng) with abcc4 mRNA (160 ng). Ctrl: Ctrl-MO (8 ng). The total numbers of embryos pooled from n = 3 independent experiments are indicated. Graph shows mean ± s.d.; Student’s t test: ∗∗∗P < 0.001. Statistics source data for Supplementary Fig. 4i, j can be found in Supplementary Table 2.
(a) Bar chart depicting percentages of phenotypically wild-type embryos in several experimental groups as indicated. lkt mutants were treated using PGE2 (50μm) or PGF2〈 (50μm) to rescue reversed heart looping (3–24 hpf), otolith defects (10–48 hpf) and hydrocephalus (10–72 hpf). The total number of embryos pooled from n = 3 independent experiments are indicated. Error bars represent mean ± s.d.; Student’s t test: ∗∗P < 0.001. NS: not significant. (b,c) cox2-MO injection (8 ng) caused hydrocephalus and curved axis (31%; n = 110), and three otoliths (21%; n = 110; arrows). (d–g) Acetylated tubulin immunostaining showing a reduction of ependymal cell cilia in the spinal canal in embryos injected with cox1-MO (e; 8 ng, n = 24), cox2-MO (f; 8ng, n = 27) and ep4-MO (g; 1 ng, n = 25), compared with control embryos at 72 hpf (d). Scale bar: 100 μm (b,c); 10 μm (d–g). (h,i) Stacked bar graphs depicting percentages of embryos with phenotypes grouped in otolith defect (h) and curved axis (i). cox1/2 morphants were incubated in PGE2 (50μM) to rescue otolith defect (10 to 48 hpf) and curved axis (10 to 72 hpf). Treatment of ep4 morphants with FSK (50 μM) but not PGE2 rescued otolith defect (10 to 48 hpf) and curved axis (10 to 72 hpf) in ep4 morphants. Ctrl: embryos injected with Ctrl-MO. The total numbers of embryos pooled from n = 3 independent experiments are indicated on the top of each bar. Yates corrected Chi-square test, ∗∗∗P < 0.001, degree of freedom = 1. NS: not significant. Statistics source data for Supplementary Fig. 5a, d, e can be found in Supplementary Table 2.
Supplementary Figure 6 Expression of foxj1a and foxj1b are not altered in embryos deficient in lkt/abcc4, cox1/cox2 or ep4 activities.
(a,b) lkt+/− heterozygous and wild-type homozygous embryos injected with different doses of cox1-MO and ep4-MO display comparable percentages of LR randomization and hydrocephalus. Embryos derived from crosses between lkt+/− heterozygotes and wild-type zebrafish were injected with cox1-MO, ep4-MO or control-MO (Ctrl). The injected embryos were genotyped using SSLP markers (Z17212) to distinguish lkt+/− heterozygous embryos (∼50%) from wild-type homozygotes. Percentages reflect the frequency of phenotypic abnormalities. The total numbers of injected embryos pooled from n = 3 independent experiments are indicated above each bar. Yates corrected Chi-square test, ∗∗∗P < 0.0001, one degree of freedom. NS: Not significant. Statistics source data for Supplementary Fig. 6a, b can be found in Supplementary Table 2. (c–f) In situ hybridization analyses revealing the comparable expression of foxj1a in DFC cells in wild-type embryos, lkt mutants, cox1/cox2 morphants or ep4 morphants at 9 hpf. (g–j) The expression of foxj1a in the spinal cord precursors (arrowhead) and rudiments of the pronephric ducts (arrows) was not altered in lkt mutants, cox1/cox2 morphants or ep4 morphants, compared with wild-type embryos at 13 hpf. (k–n) The foxj1b expression in developing otic placodes was not altered in lkt mutants, cox1/cox2 morphants or ep4 morphants compared with wild-type embryos at 13 hpf. Scale bar: 100 μm (a–l).
Histograms showing IFT88-EYFP particle velocity distribution in PGE2-treated IMCD3 cells and control cells (n > 50). Blue: Anterograde velocity; Red: Retrograde velocity. Arrows represent mean velocity in untreated cells. PGE2 treatment increased the anterograde velocity but not the retrograde velocity.
(a–d) Immunostaining analyses showing individual cilia in IMCD3 cells treated with control siRNA, ABCC4-siRNA, EP4-siRNA or PGE2. Insets reveal high-magnification images of cilia (red arrows). Green: ARL13B for cilium; Red: γ-tubulin for centrosome; Blue: DAPI; Arrow: cilium. PGE2 treatment: 10 μM; 12 h. Scale bar: 10 μm (a–d). (e,f) Immunoblot analysis showing ABCC4 or EP4 protein levels in IMCD3 cells transfected with control siRNA, ABCC4-siRNA or EP4-siRNA. (g,h) Statistical analyses of percentages of ciliated cells and average length of cilia in IMCD3 cells transfected with control siRNA (470), ABCC4 siRNA (654), EP4 siRNA (594) and control siRNA plus PGE2 (371). Student’s t-test: ∗∗P < 0.01,∗∗∗P < 0.001; error bar represents mean ± s.d.; n = 3 independent experiments with total number of cells provided in parentheses. (i,j) Bar graphs showing steady-state levels of intracellular cAMP (i) and intracellular Ca2+ (j) in IMCD3 cells treated with DMSO (314), PGE2 (303) and FSK (305). PGE2 treatment causes an increase of intracellular cAMP but not Ca2+ in IMCD3 cells. Forskolin (FSK) is used as a positive control. cAMP concentrations were measured using cAMP complete ELISA kit (ENZO, Life Science). Intracellular Ca2+ intensity levels (340/380nm) were measured using Fura-2 probe. DMSO: 0.5%; PGE2: 10 uM; Forskolin: 100 uM. Error bar represents mean ± s.d.; Student’s t-test: ∗P < 0.05,∗∗P < 0.01,∗∗∗P < 0.001; n = 3 independent experiments with total number of cells analysed provided in parentheses. Statistics source data for Supplementary Fig. 8g–j can be found in Supplementary Table 2. Uncropped images of the immunoblots are shown in Supplementary Fig. 9.
The red rectangles indicate the immunoblot fragments presented in the main body of the paper.
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This is a time-lapse of fluorescent bead movement within the KV of an 8-somite wild-type embryo. Imaged were taken at 25 frames per second using a Zeiss Axio Imager M1 microscope with a 63 × Plan Apochromat objective. (MOV 9776 kb)
This is a time-lapse of fluorescent bead movement within the mutant KV at the 8-somite stage. KV fluid flow was imaged (25 frames per second) under a 63 × Plan Apochromat objective using a Zeiss Axio Imager M1 microscope. (MOV 13409 kb)
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Jin, D., Ni, T., Sun, J. et al. Prostaglandin signalling regulates ciliogenesis by modulating intraflagellar transport. Nat Cell Biol 16, 841–851 (2014) doi:10.1038/ncb3029
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