Morphogenesis is the process whereby cell collectives are shaped into differentiated tissues and organs1. The self-organizing nature of morphogenesis has been recently demonstrated by studies showing that stem cells in three-dimensional culture can generate complex organoids, such as mini-guts2, optic-cups3 and even mini-brains4. To achieve this, cell collectives must regulate the activity of secreted signalling molecules that control cell differentiation, presumably through the self-assembly of microenvironments or niches. However, mechanisms that allow changes in tissue architecture to feedback directly on the activity of extracellular signals have not been described. Here we investigate how the process of tissue assembly controls signalling activity during organogenesis in vivo, using the migrating zebrafish lateral line primordium5. We show that fibroblast growth factor (FGF) activity within the tissue controls the frequency at which it deposits rosette-like mechanosensory organs. Live imaging reveals that FGF becomes specifically concentrated in microluminal structures that assemble at the centre of these organs and spatially constrain its signalling activity. Genetic inhibition of microlumen assembly and laser micropuncture experiments demonstrate that microlumina increase signalling responses in participating cells, thus allowing FGF to coordinate the migratory behaviour of cell groups at the tissue rear. As the formation of a central lumen is a self-organizing property of many cell types, such as epithelia6 and embryonic stem cells7, luminal signalling provides a potentially general mechanism to locally restrict, coordinate and enhance cell communication within tissues.
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We are grateful to J. Ellenberg, S. de Renzis and F. Peri for suggestions and comments on the manuscript, A. Aulehla for advice about timing, and E. Karsenti and the Gilmour laboratory for discussion. We thank M. Brand for advice about FGF tagging, the EMBL Advanced Light Microscopy Facility, in particular Y. Belyaev, for imaging assistance, the European Molecular Biology Laboratory (EMBL) Monoclonal Antibody (MACF) and Protein Expression Facilities for Fgfr1a antibody, K. Miura from the EMBL Centre for Cell and Molecular Imaging for advice with data analysis, E. Dona and T. Gregor for advice with the smFISH protocol, and A. Gruia for fish care. We acknowledge funding from the European Molecular Biology Organization and EMBL Interdisciplinary Postdocs (EIPOD) (to C.R.) and the Deutsche Forschungsgemeinschaft SFB 488 (to D.G.).
The authors declare no competing financial interests.
Extended data figures and tables
a, Posterior lateral line organs at 2 d.p.f. (cldnb:lynGFP). Organ positions were identified from intensity profiles using peakFinder_R. b, Density profile of distance between consecutive organ positions (first, second, third and fourth spacing interval; see Fig. 1a). c, List of potential parameters affecting organ spacing. d, cldnb:lynGFP and brightfield overlay image. Spheres indicate colour code representing individual organs used in further analysis. e, Upper panel, kymograph (x–t graph) from a 17.6 h time-lapse movie, where the y axis represents time and the x axis represents distance. Lower panel, segmented kymograph of primordium migration (green) and myotome growth (dashed lines) through time. f, g, Calculated position (f) and velocity (g) of each organ through time. Asterisk shows the time point when organ disengages from the migrating collective. h, Second organ acceleration through time. Organ deposition is defined as the time where acceleration is minimum. i, Growth-effect-subtracted velocity of each organ through time (solid lines) versus observed velocities (dashed line). j, Reconstruction of organ positions from growth-subtracted velocities. k, Comparing spacing, average velocity and time between consecutive depositions for first, second, third and fourth interval (normalized to maximum). l, Correlation of time, distance and average velocities between consecutive depositions. Statistics: Spearman N = 82, n = 260, x–t r2 = 0.77, x–v r2 = 0.25, v–t r2 = −0.07. Scale bars, 500 μm (a), 200 µm, 5 h (d, e).
Extended Data Figure 2 ‘Tunable’ drug-inducible gene expression with LexPR and quantification of dose-dependent response to FGF signalling.
a, Schema shows transactivator LexPR expressed under the control of CXCR4b promoter (Cxcr4b:LexPR) driving expression of LexOP-coupled coding sequences upon addition of inducer RU486 (above). Image of cxcr4b:LexPR-driven expression of lexOP:nlsGFP showing spatially restricted expression upon RU486 treatment. Scale bar, 500 μm (cry:eCFP ‘crystal eye’ marker: orange arrow; clmc2:GFP ‘bleeding heart’ marker: white arrow). b, Mean fluorescence intensity projection of Cxcr4b:LexPR, LexOP:nlsGFP primordium treated with 5 (n = 44), 10 (n = 34) and 20 μM (n = 32) RU486. Scale bar, 50 μm. Plot shows quantification of signal intensity after 4 h of RU486 induction (P5–10 = 2.53 × 10−8, P10–20 = 4.03 × 10−8). c, Colorimetric in situ hybridization of fgf3 mRNA in Cxcr4b:LexPR, LexOP:Fgf3–GFP showing uniform expression. Scale bar, 50 μm. d, e, Organ spacing in FGF inhibitor- and inducer-treated embryos at 2 d.p.f. d, Quantification of organ spacing (n = 78, 71, 74, Pctrl-05 = 6.22 × 10−14, P05-1 = 7.26 × 10−4) in SU5402-treated samples. e, Quantification of organ spacing (n = 109, 112, 119, 137, Pctrl-5 = 1.33 × 10−10, P5–10 = 7.06 × 10−4, P10–20 = 2.46 × 10−4) in RU486-treated samples. f, Organ depositions in WT and homozygous fgfr1at3R705H mutants shown by kymographs of 21 h time-lapse movies. Quantification of spacing (n = 49, 39, P = 7.69 × 10−14) and deposition timing (n = 31, 28, P = 4.64 × 10−11) between organs (first interval). Scale bar, 200 µm, 5 h.
a, cldnb:lynGFP embryos showing comparison of organ deposition and rosette formation rate upon lexOP:fgf3–GFP overexpression. b, c, Comparisons of total number of organs deposited (left) and total number of organ progenitor rosettes assembled (right) through time in control (blue) and lexOP:fgf3–GFP (red) embryos. Only organ deposition timing shows a clear difference between these conditions. c, Plots showing multiple examples of data in b (n = 7, 7).
a, Golgi, labelled by GM130-tdTomato (white) mRNA injection, are localized apically around rosette centres in lateral line primordium (cldnb:lynGFP, red). Scale bar, 20 µm. b, Maximum projection of apical optical sections of a transgenic lexOP:fgf3–GFP primordium, counterstained for ZO1, shows intracellular Fgf3–GFP signal around rosette centres in addition to luminal signal. Scale bar, 50 µm. c, Single cell expressing Fgf3–GFP feeds the central microlumen through apical secretion (expressing cell indicated with yellow dashed line). Scale bar, 5 µm. d, Mosaic primordium showing apically localized intracellular Fgf3–GFP signal co-localizes with Golgi marker GM130-tdTomato. Scale bar, 5 µm. e, Intracellular Fgf3–GFP and secGFP localization at secretory path. f, Golgi (GM130-tdTomato) co-labelling with secGFP. Scale bar, 5 µm. g, Endoplasmic reticulum (mKate2-KDEL) co-labelling with secGFP. Scale bar, 5 µm. h, Signal distribution of secGFP and Fgf3–GFP in three dimensions within the expressing cell where Golgi was taken as a central point. Comparison of Fgf3–GFP and secGFP density profiles suggests that Fgf3–GFP is more pronounced in Golgi (nsecGFP = 5, nFgf3–GFP = 4). i, Imaging of Fgf3–GFP-expressing clones (white dashed lines) with high sensitivity reveals Golgi localization (yellow arrowheads) of Fgf3–GFP in expressing cells close to the microlumen (asterisk) and intracellular vesicles in connected non-expressing cells (white arrowheads). No extracellular signal besides microluminal accumulation was detected. Scale bar, 5 µm.
Extended Data Figure 5 CLEM analysis of microlumen structure and FLIP/FRAP analysis of microluminal pools.
a, Overview of lexOP:secGFP; cxcr4b:nls-tdTomato embryo used for CLEM; two organs and migrating primordium were targeted for further processing. Scale bar, 200 μm. b, Re-sliced middle section of targeted organ centres, overlay of secGFP signal with corresponding EM slice (scale bar, 5 μm) and close-up view of microlumina. c, Close-up view of luminal cavity (green) distorted by kinocilium (blue). d, Traced tight junctions (red) and adherens junctions (orange) at three cross-sections of microlumen. e, Setup of FLIP experiment on Fgf3–GFP and secGFP pool highlighting repetitively bleached region (0.73 μm diameter, red circle) and regions used for total pool (green circle), background (grey box) and readout (blue circles) measurements. Plots show mean intensity of described ROIs over time. f, FRAP experiment on secGFP and Fgf3–GFP pools with a strip ROI. Mean normalized recovery curves (mean ± s.d., N = 7) and calculated half time of recovery. Arrow indicates start of bleaching.
a, BAC fgf3:fgf3–GFP line showing expression in known Fgf3 expression domains (28 h.p.f.). Scale bar, 200 µm. b, Loss-of-organ deposition phenotype Fgf3/10a morphant embryos (Fgf3/10a MO, upper) is rescued by BAC fgf3:fgf3–GFP transgene (lower). c, Low-magnification image showing Fgf3/10 morphants, with BAC fgf3:fgf3–GFP rescued siblings, distinguished by crystal eye transgene marker (yellow star). Scale bar, 200 µm (b). d, Quantification of rescue by comparing organ counts of WT, fgf3:fgf3–GFP with Fgf3/10 MO background and Fgf3/10a MO alone at 2 d.p.f. (NWT = 9, Nrescue = 13, NFgf3/10a_MO = 14, PWT-rescue = 0.09, Prescue-Fgf3/10a_MO = 1.751 × 10−6).
a, Kymographs of mosaic Fgf3–GFP expression generated via cell transplantation. lexOP:fgf3–GFP/cxcr4b:nls-tdTomato-expressing clones (green) in the cldnb:lynGFP line (red) cause rapid arrest of migration. The phenotype only becomes apparent when the organ reaches tissue rear. (Colour code: organs with ectopic FGF source in green; organs without ectopic FGF source in red; organs of control transplants in blue.) Scale bars, 200 µm, 5 h. b, Quantification of spacing and deposition timing of organs from mosaic Fgf3–GFP transplants, normalized by mean values of control embryos for each interval (Ncontrol = 7, Ntransplants = 8, ncontrol = 25, nneg = 17, npos = 13; spacing: Pctrl–neg = 0.24, Pctrl–pos = 1.43 × 10−5, Pneg–pos = 4.40 × 10−5; timing: Pctrl–neg = 0.07, Pctrl–pos = 1.23 × 10−6, Pneg–pos = 4.09 × 10−5). c, Close-up view of Fgf3–GFP (green)/nls- tdTomato- (red) expressing clones in cldnb:lynGFP- (green) expressing organ, showing cells in different positions feed in the central microlumen. Scale bar, 5 µm. d, Tracking of WT transplanted cells (nuclei marked with grey dots and numbered) relative to organ centres in cldnb:lynGFP primordium (red). Yellow circles represent each organ unit. Middle panel: calculated velocities for each tracked nucleus (grey lines) and organ centres (green lines) reveal that migration of individual cells is in synchrony with the belonged organ unit independent of their position. Right panel: distance between consecutive tracked cells at the beginning and end of the time-lapse movie shows that initial distance is not a reliable indicator of final cell positions.
a, Pea3 smFISH on WT, 15 μM FGF inducer- and 4 μM FGF inhibitor-treated primordia (cldnb:lynGFP in green, DAPI staining in blue, pea3 mRNAs in white), Scale bar, 5 μm. Close-up view of the dashed boxes shown as raw image (middle) and segmented pea3 transcripts (right). Scale bar, 2 μm. b, Image of pea3 smFISH in WT primordium (above); profile plot shows pea3 transcripts per cell over distance from leading edge (below). c, Pea3 smFISH in an organ with single Fgf3–GFP-expressing cell. Number of pea3 transcripts assigned to each nucleus does not show increase towards the expressing cell. Scale bar, 5 μm. d, Colorimetric in situ hybridization of pea3 mRNA showing high expression levels upon Fgf3–GFP induction, visible after 1 h colour reaction (30 °C), whereas expression in WT is hardly detectable. However, increasing reaction time reveals pea3 mRNA signal in WT primordia. e, Colorimetric in situ hybridization (30 °C, 0.5 h) of pea3 RNA in mosaic Fgf3–GFP expression shows detectable pea3 only in the expressing organ. Scale bar, 100 µm.
Extended Data Figure 9 Characterization of luminal integrity and function upon mechanical and genetic perturbation.
a, Plot of secGFP pool fluorescence intensity upon micropuncture (green). Kymographs show the time-lapse imaging of the secGFP pool used for the plot. b, c, Luminal Fgf3–GFP signal recovery of whole pool bleached (left) and micro-punctured (right) organs during 48 min of acquisition. Kymographs show time-lapse imaging of Fgf3–GFP pool. Single time points of time-lapse imaging after micro-puncture (right). Scale bar, 5 μm. d, Quantification of pea3 transcript levels at t = 0 h, 1 h and 4 h after micropuncture of organ 2 expressing lexOP:fgf3–GFP. Unperturbed organ 3 was used for normalization. Comparison of control and punctured organs suggests that pea3 levels are normal immediately after puncture, are reduced 1 h later and recovered by 4 h (N0 h puncture = 6, N0 h control = 5, N1 h puncture = 6, N1 h control = 5, N4 h puncture = 6, N4 h control = 5, P0 h = 0.7922, P1 h = 0.0043, P4 h = 0.4286). e, Organ deposition delay upon lumina micropuncture of secGFP-expressing second and third organs (Nctrl second organ = 22, Npuncture second organ = 23, Nctrl third organ = 8, Npuncture third organ = 9, Psecond organ = 6.928 × 10−6, Pthird organ = 0.0061). Scale bar, 200 µm. f, g, Shroom3 morphant primordia show intervals with no or delayed deposition. f, Kymographs of shroom3 MO and control. Scale bars, 200 µm, 5 h. g, Organ pattern in shroom3 MO and control at 2 d.p.f. Scale bar, 200 µm.
a, Microlumen of maturing organs fuses with the skin and the diffusible content (Fgf3–GFP in green) disappears. Tight junctions marking microlumen and skin borders are revealed by ZO1 immunofluorescence (red). Cartoon displaying the sequence of events (right). Scale bar, 5 µm. b, Kymograph and single time-points from time-lapse imaging of secGFP, nls-tdTomato-expressing embryo. SecGFP signal disappears as microlumen opens (arrowheads in kymograph show opening of microlumina). Scale bars, 200 µm, 5 h. c, Side view of a maturing organ with kinocilia protruding out of the organ (cldnb:lynGFP in green, central cell atoh1a:tdTomato in red). Scale bar, 5 μm.
Embryo growth, primordium migration velocity and organ deposition timing are the potential parameters to underlie organ spacing. Time-lapse movie of cldnb:lynGFP embryo (bright field lower panel and fluorescence imaging upper panel). Corresponds to Extended Data Fig. 1e. Scale bar = 200 μm. Time interval = 20 min. (MOV 3188 kb)
Organs were tracked automatically using signal intensity profiles of cell membranes based on a peak detection method. Upper panel is time-lapse movie of cldnb:lynGFP embryo and lower panel is maximum intensity profile along the thickness of the upper panel image over time. Relates to Method "analysis of migration and organ patterning". Scale bar = 100 μm. Time interval = 10 min. (MOV 1107 kb)
Decreasing FGF signaling with FGFR1 inhibitor increases organ deposition time in a dose-dependent way
Time-lapse movies of FGF inhibitor treated embryos (DMSO control, 0.5 μM and 1 μM SU5402 treatments). Corresponds to Fig 1d. Scale bar 100 μm. Time interval = 10 min. (MOV 885 kb)
Time-lapse movies of fgfr1at3R705H mutant embryos. Corresponds to Extended Data Fig. 2. Scale bar = 100μm. Time interval = 10 min. (MOV 398 kb)
Time-lapse movies of FGF inducer treated embryos. (10 μM RU486 treated no target gene carrier control, 5, 10, 20 μM RU486 treated Fgf3-GFP transactivation treatments) Corresponds to Fig1e. . Scale bar = 100 μm. Time interval = 10 min. (MOV 1266 kb)
Time-lapse movies of secGFP and Fgf3-GFP expressing embryos with red nuclei counter-label. Panel 1 and 4 corresponds to Figure 2b. Second movie panel shows luminal opening of organ 1, corresponds to Extended Data Fig.10b. Scale bar 100 μm. Time interval = 25 min. (MOV 612 kb)
3D stacks of EM images of an organ center, secGFP overlay with EM stacks, luminal space and kinocilia segmentation and overlay of segmented microlumina with secGFP signal are shown. Relates to Method "correlative light-electron microscopy". Scale bar indicated in the movie. (MOV 589 kb)
Time-lapse movie showing that ectopic Fgf3-GFP3 expressing clones (bottom, in green) accelerate the deposition of individual organs. (membrane counter-label in red). Corresponds to Extended Data Fig. 7a. Scale bar = 100 μm. Time interval = 30 min. (MOV 280 kb)
Volume masking of lateral line tissue and spot segmentation of nuclei and smFISH signal (membranes in green, nuclei in blue and pea3 transcripts in grey). Relates to Method "single molecule fluorescent in situ hybridization". Scale bar = 10 μm. (MOV 495 kb)
Time-lapse movie shows Fgf3-GFP leakage upon micropuncture (Fgf3-GFP green, lynRFP red). Arrow indicates image acquired right after the laser pulse. Corresponds to Figure 4c. Scale bar = 5 μm. Time interval = 0.5 sec. (MOV 642 kb)
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Durdu, S., Iskar, M., Revenu, C. et al. Luminal signalling links cell communication to tissue architecture during organogenesis. Nature 515, 120–124 (2014). https://doi.org/10.1038/nature13852
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