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Cadherin-dependent filopodia control preimplantation embryo compaction

Nature Cell Biology volume 15, pages 1424–1433 (2013)Cite this article

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Abstract

Compaction of the preimplantation embryo is the earliest morphogenetic process essential for mammalian development, yet it remains unclear how round cells elongate to form a compacted embryo. Here, using live mouse embryo imaging, we demonstrate that cells extend long E-cadherin-dependent filopodia on to neighbouring cells, which control the cell shape changes necessary for compaction. We found that filopodia extension is tightly coordinated with cell elongation, whereas retraction occurs before cells become round again before dividing. Laser-based ablations revealed that filopodia are required to maintain elongated cell shapes. Moreover, molecular disruption of the filopodia components E-cadherin, α- and β-catenin, F-actin and myosin-X prevents cells from elongating and compacting the embryo. Finally, we show that early filopodia formation triggered by overexpressing myosin-X is sufficient to induce premature compaction. Our findings establish a role for filopodia during preimplantation embryonic development and provide an in vivo context to investigate the biological functions of filopodia in mammals.

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Figure 1: E-cad filopodia form during mouse embryo compaction.
Figure 2: Filopodia distribution patterns imaged with two-photon excitation (2PE) microscopy.
Figure 3: Filopodia extension–retraction dynamics are tightly coordinated with cell shape changes during compaction.
Figure 4: Filopodia laser-ablation perturbs cell shape.
Figure 5: Molecular disruption of filopodia perturbs cell shape and compaction.
Figure 6: Myo10 is required for filopodia formation during compaction.
Figure 7: Premature filopodia formation induces early compaction.

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Acknowledgements

We thank A. Yap, E. Jesudason, A. Fouras and J. Polo for comments on the manuscript; T. Bell for advice on laser ablations; S. Firth and I. Harper for help with imaging experiments; and R. Cheney, A. Yap and B. Henderson for sharing DNA constructs. N.P. is supported by ARC DP120104594 and DE120100794, NHMRC APP1052171 and Monash University Strategic and Interdisciplinary grants, and J.C.F-G. by Wenner-Gren Foundations and Swedish Society for Medical Research Postdoctoral Fellowships.

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Author notes

  1. Juan Carlos Fierro-González and Melanie D. White: These authors contributed equally to this work

Authors and Affiliations

  1. European Molecular Biology Laboratory, Australian Regenerative Medicine Institute, Level 1 Building 75, Monash University, Victoria 3800, Australia

    Juan Carlos Fierro-González, Melanie D. White, Juan Carlos Silva & Nicolas Plachta

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  1. Juan Carlos Fierro-González
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  2. Melanie D. White
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  3. Juan Carlos Silva
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  4. Nicolas Plachta
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Contributions

J.C.F-G. and M.D.W. designed and performed the experiments. J.C.S. performed embryo microinjections and manipulations. N.P. supervised the project. J.C.F-G., M.D.W. and N.P. wrote the paper.

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Correspondence to Nicolas Plachta.

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Integrated supplementary information

Supplementary Figure 1 Characterization of filopodia with membrane-targeted mCherry, DIC, F-actin, α-cat and β-cat.

a, b, Filopodia length and number in embryos microinjected with E-cad-GFP or memb-mCherry RNA. In a, n = 21 filopodia for E-cad-GFP; 23 for memb-mCherry. In b, n = 18 cells for E-cad-GFP; 12 for memb-mCherry. c, E-cad-GFP colocalizes with memb-mCherry in filopodia. d, Representative example of live embryos labelled with memb-mCherry in half of the cells at different developmental stages. Filopodia (arrowheads) are only detectable during compaction (8- to 16-cell stage). n = 20 embryos. e, Three-dimensional surface renders of embryo from Fig. 1e. Filopodia extend from the border membrane region between the AJ and apical domain of the filopodia-forming cells on top of the neighbouring cell apical membrane (not labelled in this example). f, Visualization of filopodia (arrowheads) by DIC. Images in g, i, j and k are from live 8-cell stage embryos microinjected into one cell at the 2-cell stage with RNAs to express E-cad-RFP and Lifeact-GFP (g), GFP- α-cat (i), β-cat-GFP (j) and GFP- α-tubulin (k). Images in h, l are from non-injected, fixed 8-cell stage embryos, double-stained with E-cad antibodies (E-cad IF) and rhodamine-phalloidin (h) or α-tubulin antibodies (l). g, E-cad-RFP-labelled filopodia are enriched in F-actin revealed by Lifeact-GFP fluorescence in a live embryo. Arrow shows detection of filopodia in a low-magnification 3-dimensional view of the embryo. Yellow-boxed image shows higher-magnification view of the filopodia. h, Co-localization of E-cad and rhodamine-phalloidin. i–k E-cad-RFP also co-localizes with α- and β-cat fused to GFP (i, j), but not with GFP- α-tubulin (k) in filopodia. l, E-cad does not co-localize with α-tubulin in filopodia. Yellow-boxed images in g, h and l show higher-magnification views to better visualize some of the filopodia. n.s., not significant by t test. Error bars represent s.e.m. Statistics source data for a and b can be found in Supplementary Table 1. Horizontal and orthogonal scale bars, 5 μm.

Supplementary Figure 2 Filopodia do not extend simultaneously between neighbouring cells and they retract before cell division.

a, Schematic experimental design. Each cell of a 2-cell stage embryo is microinjected with either E-cad-GFP or memb-mCherry. b, Representative example of a live, early 8-cell stage embryo, microinjected at the 2-cell stage as described in a comprising four E-cad-GFP-positive and four memb-mCherry-positive cells. c, Representative example of a cell expressing memb-mCherry extending filopodia on top of an E-cad-GFP-positive cell. d, Representative converse situation to that in c, showing a cell expressing E-cad-GFP extending filopodia on top of a memb-mCherry-positive cell. Note that in c and d the cell receiving filopodia does not extend reciprocal filopodia onto the filopodia-forming cell. Analysis of multiple embryos manipulated as described in this figure revealed complete absence of reciprocal filopodia extension between cells of the embryo (n = 8 embryos). e, Selected 3-dimensional reconstructions of a live embryo (8-cell stage) microinjected at the 1-cell stage with E-cad-GFP and H2B-RFP RNAs. For simplicity of illustration, the H2B-RFP signal is only shown for the cell of interest. The H2B-RFP-labeled cell is a filopodia-forming cell, as at time 0 min it is extending filopodia (arrows) on top of its neighbours. Prior to undergoing division the cell retracts its filopodia. The mitotic events can be followed by condensation of the H2B-RFP-labeled chromatin (right panel) and the divisions of the two daughter nuclei (left panel). As illustrated in these examples, we never observed filopodia from neighbouring cells extending on top of a cell engaged in cell division (n = 30 cells in 15 embryos). f, The same pattern of filopodia retraction prior to division of the filopodia-forming cell is obtained when viewing embryos in which filopodia-forming cells and their neighbours are labeled with either E-cad-GFP or memb-mCherry microinjected as described in a. Note that also as illustrated in this example, neighbouring cells (red) do not extend filopodia on top of the cell engaged in division (green). Orthogonal scale bars, 5 μm.

Supplementary Figure 3 Two-cell stage blastomeres contribute filopodia-forming cells to variable extents.

a, Schematic representation of the experimental approach (left panel). Only one cell was microinjected at the 2-cell stage with memb-mCherry and the contribution of filopodia-forming cells by that single cell was then assessed during compaction. Each data point in the graph represents a single embryo. The scattered distribution pattern of the data suggests no obvious systematic contribution of filopodia-forming cells by the original 2-cell stage blastomeres. Individual 2-cell stage blastomeres can contribute filopodia-forming cells to variable extents (n = 24 embryos). b–e, Selected frames over time show a filopodia-forming cell (in white) undergoing symmetric (b) or asymmetric (d) division (n = 13 cells in 11 embryos). During symmetric division the two daughter cells are allocated to the outer, extraembryonic regions (c), while in asymmetric division, one of the daughter cells becomes internalized to the pluripotent region (e). Embryos were microinjected with memb-mCherry as described in a. Arrowheads depict filopodia. Horizontal and orthogonal scale bars, 5 μm.

Supplementary Figure 4 Extensive AJ ablations do not alter the shape of the apical border adjacent to filopodia.

a, Immediately following AJ laser ablation (yellow brackets in b), the angle of the cell membrane (blue angle) in the apical border region where filopodia extended (yellow arrowheads) remains unchanged. b, A different focal plane of the same cell shown in a depicts the AJ region where laser ablation was performed (yellow brackets). c, Transmitted light imaging at the same focal plane as b shows that the two adjacent cells fused (white arrow) following ablation. Embryos were microinjected with memb-mCherry into one cell at the 2-cell stage. d,Lack of fluorescence recovery following laser ablation. Cells expressing memb-mCherry were ablated at the AJ with 20% laser intensity transmission. Fluorescence recovery in the irradiated region is observed with 5%, but not 20% transmission indicating complete ablation is achieved with 20%. Vertical lines represent mean ± s.e.m (n = 3 cells from 3 different embryos per treatment). Scale bars, 5 μm.

Supplementary Figure 5 Expression and manipulation of endogenous E-cad, α-cat, β-cat, F-actin and Myo10.

a, Efficient knockdown of endogenous E-cad, α- and β-cat by microinjection of siRNAs into one cell of the embryo at the 2-cell stage (n = 18 cells for Control siRNA, 6 for E-cad siRNA, 15 for α-cat siRNA, and 8 for β-cat siRNA), as measured by immunofluorescence (IF). b, Knockdown of α- or β-cat significantly downregulates E-cad protein (n = 6 cells for Control siRNA, 15 for α-cat siRNA, and 8 for β-cat siRNA). In a and b, a scrambled control siRNA did not alter protein levels; non-injected cells were used as internal control. ***P<0.001 by t test. Error bars represent s.e.m. c–e, Selected single plane images show the knockdown effects measured in a and b. f, Knockdown of endogenous α- and β-cat results in fewer filopodia. g, The fewer filopodia that still form in cells microinjected with E-cad siRNA display overall elongation-retraction dynamics similar to control cells. Selected time frames from an embryo microinjected with E-cad siRNA and memb-mCherry into one cell at the 2-cell stage. Two neighbouring cells extend a single filopodium each on top of a non-injected cell (unlabeled in this example). Yellow and blue arrows distinguish each filopodium. Note that the time window used to image these cells was sufficient to capture the division of the lower cell extending the yellow-marked filopodium following filopodia retraction. The timing of filopodia elongation and retraction are overall similar to those recorded for control cells in Fig. 1f. h–m. Molecular manipulations of filopodia components prevent cells from integrating into the compacting embryo. h,i, Cells microinjected with siRNAs against α- or β-cat (h) or with E-cad ΔECD-RFP (i) fail to integrate into the compacting embryo and remain rounded. j–l, Cells in embryos treated with the E-cad antibody (j) or cytochalasin D (CD) at 3 μg/ml (k) or 0.5 μg/ml (l) remain rounded and embryos fail to compact. In k, following 3 μg/ml CD washout embryos fail to extend filopodia and their cells remain rounded, while following 0.5 μg/ml CD washout in l embryos extend normal-appearing filopodia and resume compaction (see also Fig. 5). In h embryos were co-microinjected with memb-mCherry into one cell at the 2-cell stage. In j–l, memb-mCherry was injected into half of the cells to visualize filopodia and cell shape. m, Percent of embryos displaying defects in compaction when subjected to the different molecular manipulations shown in panels h–l and Fig. 5b. ***P<0.001;**P<0.01; n.s., not significant by Fisher’s exact test (see Methods for a detailed explanation on statistical analyses). n, E-cadΔECD-RFP does not accumulate at regions where filopodia normally extend. Unlike E-cad-RFP, E-cadΔECD-RFP is not enriched at regions where filopodia normally extend. Apical membrane regions of the same embryo were used as internal control (n = 11 cells for E-cad-RFP, and 12 for E-cadΔECD-RFP). ***P<0.001 by t test. Error bars represent s.e.m. o, Selected rainbow images represent the changes in expression shown in n. p, Example of detached filopodia in embryo treated with the E-cad antibody DECMA1. Representative Z projection showing a clearly detached filopodium (arrowhead) projecting outwards from the embryo towards the zona pellucida (ZP). The embryo was microinjected into one cell of the 2-cell stage with memb-mCherry and treated with the DECMA1 antibody. q, The defects in compaction caused by the E-cad and Myo10 siRNAs can be rescued by ∼ 27% in the presence of E-cad-GFP or GFP-Myo10, respectively. *P<0.05 by Fisher’s exact test. r, Efficiency of knockdown with Myo10 siRNAs microinjected into one cell at the 2-cell stage (n = 12 cells for Control siRNA, and 11 for Myo10 siRNA), as measured by immunofluorescence (IF). ***P<0.001 by t test. Error bars represent s.e.m. s, Selected rainbow images show the knockdown effects measured in r. Statistics source data for a, b, m, n, q and r can be found in Supplementary Table 1. Orthogonal and horizontal scale bars, 5 μm.

Supplementary Figure 6 Effects of cytochalasin D and nocodazole treatments.

a, Representative images of Lifeact-GFP fluorescence following treatment with Cytochalasin D (CD). CD at 3 μg/ml largely depletes Lifeact-GFP fluorescence. CD at 0.5 μg/ml reduces, but does not completely deplete Lifeact-GFP fluorescence. A 4-hour incubation in KSOM+AA (4h wash) restores Lifeact-GFP expression only in embryos treated with 0.5 μg/ml CD. b, Quantification of Lifeact-GFP fluorescence along the cell membrane. In b, n = 22 cells for 3 μg/ml CD; 15 for 0.5 μg/ml CD; 19 for 4 h wash. ***P<0.001; **P<0.01 by t test. Error bars represent s.e.m. c, Filopodia number per neighbouring cell is not significantly higher in embryos treated with 0. 5 μg/ml CD, when compared to that observed after 4h wash. (see Fig. 2 and Supplementary Fig. 1 for comparison with untreated embryos). In c, n = 17 cells for 4 h CD (0.5 μg/ml); 7 cells for 4 h wash. n.s., not significant by t test. d, Representative examples of detached filopodia in embryos treated with 0.5 μg/ml CD. Upper panel shows a single focal plane, lower panel shows 3-dimensional view. Detached filopodia (arrowheads) often extend away from the embryo and contact the zona pellucida (ZP). e, Representative examples of a cell in an embryo treated with 0.5 μg/ml CD showing Lifeact-GFP in the abnormally long and detached filopodia (shown by arrow). Four hours following CD washout cells extend new filopodia showing normal Lifeact-GFP fluorescence. Insets show higher-magnification views of the filopodia indicated by arrows, which are comparable to the control situation in Supplementary Fig. 1g. f, Representative examples of E-cad-GFP distribution pattern following 0.5 μg/ml CD. E-cad-GFP displays a more punctated clustered pattern throughout the cell membrane and along filopodia. Four hours following CD washout cells extend new filopodia showing normal E-cad-GFP fluorescence distribution. Insets show higher-magnification views of the filopodia indicated by arrows. g, Embryos treated with 3 μg/ml nocodazole for 4 hours form normal filopodia and undergo compaction. Images show representative examples of embryos treated with nocodazole, which are indistinguishable from control embryos and undergo normal compaction (n = 12 embryos). Note the marked decrease in GFP- α-tubulin fluorescence in the nocodazole-treated embryos. Single focal planes are shown for DIC to appreciate compacted morphology. Statistics source data for b and c can be found in Supplementary Table 1. Horizontal and orthogonal scale bars, 5 μm.

Supplementary information

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Filopodia dynamics during mouse embryo compaction.

Time-lapse imaging of a representative embryo during compaction shows two cells extending filopodia, which then fully retract before cell division. The embryo was microinjected with memb-mCherry into one cell at the 2-cell stage. Orthogonal scale bar, 5 μm. (AVI 213 kb)

E-cad-labelled filopodia retract to the filopodia-forming cell.

Time-lapse imaging of a representative embryo during compaction shows a cell (left) with E-cad-GFP-expressing filopodia extended onto its E-cad-GFP-labelled neighbouring cell (right). The long finger-like processes clearly retract and return to the membrane apical border region where filopodia initially attached (left). Orthogonal scale bar, 5 μm. (AVI 437 kb)

Filopodia retraction occurs before cell division.

Time-lapse imaging of a representative embryo during compaction shows two cells retracting their memb-mCherry-labelled filopodia just prior to division. H2B-Cerulean-labelled nuclei show chromatin condensation and chromosome separation at the time when filopodia start to retract. Orthogonal scale bar, 5 μm. (AVI 1060 kb)

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Fierro-González, J., White, M., Silva, J. et al. Cadherin-dependent filopodia control preimplantation embryo compaction. Nat Cell Biol 15, 1424–1433 (2013). https://doi.org/10.1038/ncb2875

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