Tissue sculpting during development has been attributed mainly to cellular events through processes such as convergent extension or apical constriction1,2. However, recent work has revealed roles for basement membrane remodelling in global tissue morphogenesis3,4,5. Upon implantation, the epiblast and extraembryonic ectoderm of the mouse embryo become enveloped by a basement membrane. Signalling between the basement membrane and these tissues is critical for cell polarization and the ensuing morphogenesis6,7. However, the mechanical role of the basement membrane in post-implantation embryogenesis remains unknown. Here we demonstrate the importance of spatiotemporally regulated basement membrane remodelling during early embryonic development. Specifically, we show that Nodal signalling directs the generation and dynamic distribution of perforations in the basement membrane by regulating the expression of matrix metalloproteinases. This basement membrane remodelling facilitates embryo growth before gastrulation. The establishment of the anterior–posterior axis8,9 further regulates basement membrane remodelling by localizing Nodal signalling—and therefore the activity of matrix metalloproteinases and basement membrane perforations—to the posterior side of the embryo. Perforations on the posterior side are essential for primitive-streak extension during gastrulation by rendering the basement membrane of the prospective primitive streak more prone to breaching. Thus spatiotemporally regulated basement membrane remodelling contributes to the coordination of embryo growth, morphogenesis and gastrulation.
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The source data used in all graphs are provided in the Source Data files. Raw image files are available from the corresponding author upon request.
The codes used in this study are available at https://github.com/darogan/Kyprianou_Zernika-Goetz and https://doi.org/10.5281/zenodo.3610335.
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We thank D. Glover, M. Shahbazi and M. Zhu for valuable discussions; A. Cox for drawing the model in Fig. 4i; M. Kuehn for the Nodalfl/fl mice and V. Kouskoff for the T-GFP mice. D.S.B. is supported by the FNRS; W.N. is supported by WELBIO; I.M. is a FNRS research associate and an investigator of WELBIO. The M.Z.-G. laboratory is supported by grants from the European Research Council (669198) and the Wellcome Trust (098287/Z/12/Z).
The authors declare no competing interests.
Peer review information Nature thanks Elizabeth Lacy, Patrick Tam and Kenneth Yamada for their contribution to the peer review of this work.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Extended data figures and tables
a, Tracked bright-field stills from a time-lapse video of an E5.5–E5.75 embryo showing egg-cylinder growth along the embryo proximal–distal axis. Tracks are arbitrarily colour-coded and follow growth in xy dimensions of specific anatomical characteristics. Red, ectoplacental cone–extraembryonic ectoderm boundary; magenta–cyan, extraembryonic ectoderm; green, epiblast–extraembryonic ectoderm boundary; white–yellow, epiblast; blue, distal epiblast. n = 5 embryos. b, E5.5 embryos cultured for 8 h in the presence or absence of collagenase IV. c, Egg-cylinder aspect ratio comparison in control and collagenase IV-treated embryos. Unpaired Student’s t-test; ****P < 0.0001; mean ± s.e.m. In b and c, n = 11 (control) and 11 (collagenase IV-treated) embryos. d, Representative example of an E5.5 embryo stained for different components of basement membrane. Basement membrane perforations can be identified with all markers. n = 10 embryos. e, Representative examples of E5.5 embryos (n = 20) showing the size of basement membrane perforations relative to the size of nuclei. Asterisks, visceral endoderm nuclei; arrowheads, basement membrane perforations. f, Quantification of basement membrane perforations and cell nuclei area. n = 1,501 perforations and 100 nuclei from 6 embryos. Two-sided unpaired Student’s t-test; ****P < 0.0001; mean ± s.e.m. g, Quantification of basement membrane perforation size during post-implantation development. Average perforation size remains the same in early post-implantation stages but increases in the pre-gastrula stages. n = 423 (E5.0), n = 1,046 (E5.25), n = 1,327 (E5.5), n = 1,501 (E5.75), n = 1,615 (E6.0–E6.5). One way ANOVA; ****P < 0.0001; mean ± s.e.m. Scale bars, 20 μm.
a, AVE position and basement membrane remodelling using transgenic Cerberus–GFP embryos for AVE identification. n = 23 embryos. b, Quantification of basement membrane area covered by perforations at regions away (proximal or posterior) or close to the AVE side as in Fig. 2b, with embryos from different AVE migration stages pooled together. Two-sided unpaired Student’s t-test; ****P < 0.0001. In box plots, centre lines show median values, box limits represent the upper and lower quartiles, and whiskers show the range of values. c, Representative examples of E6.5 pre-gastrula control (n = 20 embryos) and Ttr-cre;Rhoafl/− embryos (n = 7 embryos). Blocking AVE migration results in abnormal distribution of basement membrane perforations. d, Representative examples of control (n = 5) and Ttr-cre;Rhoafl/− (n = 5) E5.5 embryos. Scale bars, 20 μm.
a, Representative examples of control Nodalfl/flcreERT2 embryos (n = 8 embryos) fixed and stained immediately upon recovery. In the absence of tamoxifen treatment, Nodalfl/flcreERT2 embryos have a normal basement membrane appearance, as Nodal expression is not affected. Bottom, position of AP axis and basement membrane perforation patterning. Arrowheads, AVE. b, Representative examples of control embryos (n = 20) and embryos treated with Nodal inhibitor (n = 22). Note the absence of basement membrane perforations and the appearance of accumulated fibrillar laminin in embryos treated with Nodal inhibitor (SB431542). c, Percentage of embryos with basement membrane perforations appearance in control embryos and embryos treated with Nodal inhibitor (SB431542). χ2 test; ****P < 0.0001. d, LifeAct-GFP ES cells cultured in conditions to maintain pluripotency (FC + 2i-LIF) and conditions to induce exit from pluripotency (FC − 2i-LIF) plated on Cy3–gelatin; three examples for each condition (1, 2, 3 and 1′, 2′ and 3′). The stripy appearance of gelatin is a result of the way it is plated. Three independent experiments. e, Representative example from three independent experiments of Cy3–gelatin remodelling by LifeAct-GFP ES cells upon exit from pluripotency. Arrowheads point to actin enrichment (invadopodia-like structures) colocalizing with region of remodelled ECM. f, Control and SB431542-treated ES cells plated on Cy3–gelatin and cultured in conditions to allow exit from pluripotency. Right, magnified images showing colocalization of control ES cells with Cy3–gelatin perforations. g, Quantification of results in f, showing amount of Cy3–gelatin remodelling based on the percentage of fluorescence that is absent. n = 7 regions for each condition. Two-sided unpaired Student’s t-test; ****P < 0.0001; mean ± s.e.m. Scale bars, 20 μm.
a, UMAP showing distribution of cells by embryonic age. n = 1,724 cells; n = 331 (E5.25), 269 (E5.5), 321 (E6.25), 803 (E6.5) cells. b, Marker genes identify epiblast (Pou5f1), extraembryonic ectoderm (Bmp4) and visceral endoderm (Amn) cells in the UMAP. n = 775 epiblast cells, 283 extraembryonic ectoderm cells and 666 visceral endoderm cells. c, Expression levels of MMP genes on UMAP plot for E5.25–E6.5. Expression values are log(counts). Blue box, epiblast. d, mRNA levels of Cerberus and Mmp25 at the anterior and posterior side of the embryo. Anterior and posterior identity was defined based on Cerberus expression. Mmp25 is highly expressed at the anterior side of the embryo. n = 3 embryos. Two-sided unpaired Student’s t-test. Cerberus: **P = 0.001; Mmp25: ***P = 0.0002; mean ± s.e.m. e, E5.5 and E6.5 pre-gastrula embryos stained for MMP14. White arrowheads, prospective primitive streak. n = 10 embryos for each stage. Scale bars, 20 μm. f, The matrix of reads per kilobase of transcript per million mapped reads (RPKM) from GSE109071 was used to calculate gene-expression correlation between pairs of genes. Epiblast cells at E6.25 and E6.5 (n = 527 cells) were extracted from the matrix and Pearson's correlation coefficient (R) with two-sided P value are given for each comparison. The points are coloured by density (kde2d).
a, Expression levels for ECM genes are plotted on the UMAP for all cell types from E5.25–E6.5 (n = 1,724 cells). All expression values are shown as log(counts). b, Representative examples of FISH for control (n = 3) and SB431542-treated embryos (n = 3). Embryos were recovered at E5.75 and cultured for 18 h before fixation. Nodal signalling is inhibited after treatment with SB431542, as shown by the absence of Nodal and Tdgf1 mRNA. c, Representative examples of control (n = 5) and Nodal inhibitor-treated (n = 5) (18 h) embryos stained for MMP14. d, Western blot analysis for MMP2 and MMP14 in control and Nodal-inhibited (SB431542) ES cells. n = 3 independent experiments. For gel source data, see Supplementary Fig. 1. e, Quantification of relative protein levels based on western blots of ES cells in the presence or absence of the Nodal inhibitor SB431542. Two-sided unpaired Student’s t-test. MMP2, **P = 0.0088; MMP14, **P = 0.0086; n = 3 independent experiments; mean ± s.e.m. f, ChIP tracks for Smad2/3. Smad2/3 binding on MMP2 and MMP14 is lost upon Nodal inhibition (green rectangles). Scale bars, 20 μm.
a, CRISPR–Cas9 exon 1 ATG initiation codon-deletion strategy. gRNAs designed to flank a 330-bp region that includes the ATG initiation codon. Genotyping primers positions are shown as arrows below the exon region. b, Genotyping results of two clones: in one, the exon remained uncut (clone 24), and in the other (clone 38), it was successfully cut. c, Western blot for MMP14 in clone 38 shows successful MMP14 protein depletion. For gel source data see Supplementary Fig. 1. d, Representative examples of control and Mmp14-knockout (KO) Lifeact-GFP ES cells stained for MMP14. MMP14 protein is not detected in the Mmp14-knockout cells. Three independent experiments. e, Representative examples of control and Mmp14-knockout Lifeact-GFP ES cells plated on Cy3–gelatin. Right, magnified images showing colocalization of control and wild-type ES cells with Cy3–gelatin perforations. Note the defective extracellular matrix remodelling in MMP14-knockout ES cells. The striped appearance of gelatin is a result of how it is plated. Three independent experiments. f, Quantification of Cy3–gelatin remodelling in e based on the percentage of absent fluorescence. Two-sided unpaired Student’s t-test; ***P < 0.001; n = 5 regions for FC and 7 regions for Mmp14 knockout; mean ± s.e.m. Scale bars, 20 μm.
a, Stills from time-lapse video of representative control (n = 5) and MMP inhibitor-treated (n = 4) (100 μM NSC405020 + 20 μM prinomastat) embryos cultured from E5.75 for 18 h. Red arrowheads show cell death initiation after growth restriction in the absence of MMP activity. b, Control (n = 20) and MMP inhibitor-treated (n = 18) embryos (18 h). c, Quantification of embryo length (18 h of culture). n = 20 control and 18 MMP-inhibitor-treated embryos; two-sided unpaired Student’s t-test; ****P < 0.0001; mean ± s.e.m. d, Representative examples of control (n = 7) and MMP inhibitor-treated (n = 6) embryos stained for the apoptotic marker cleaved caspase-3 (c-Casp3). e, Quantification of apoptotic index (number of apoptotic cells per total cell number). n = 7 control and 6 MMP inhibitor-treated embryos. Two sided unpaired Student’s t-test; ***P = 0.0002; mean ± s.e.m. f, Representative examples of control (n = 10) and MMP inhibitor-treated (n = 10) embryos stained for the mitotic marker phosphorylated histone H3 (Ser10). g, Quantification of mitotic index (number of mitotic cells per total cell number). n = 10 control and 10 MMP inhibitor-treated embryos. Two-sided unpaired Student’s t-test; mean ± s.e.m. Scale bars, 20 μm.
a, Representative examples of control and MMP inhibitor (100 μM NSC405020 + 20 μM prinomastat)-treated (treatment started at 48 h after removal of 2i-LIF for 18 h) ES cell spheroids in Matrigel. n = 3 independent experiments. b, Quantification of ES cell-spheroid area in control and NSC405020 + prinomastat conditions. Reduction of Matrigel concentration results in partial rescue of the phenotype produced upon inhibition of MMP activity. Two-sided unpaired Student’s t-test; ****P < 0.0001; mean ± s.e.m. n = 200 spheroids for each condition. c, Examples of control and NSC405020 + prinomastat-treated (treatment at 48 h) ES cell spheroids stained for cleaved caspase-3 (c-Casp3) to monitor apoptosis. n = 3 independent experiments. d, Bright-field images of wild-type and Mmp14-knockout ES cell spheroids in Matrigel 48 h after 2i-LIF removal. n = 3 independent experiments. e, Quantification of ES cell-spheroid area in wild-type and Mmp14-knockout ES cells. n = 607 wild-type and 600 Mmp14-knockout spheroids. Two-sided unpaired Student’s t-test; ****P < 0.0001; mean ± s.e.m. f, Representative examples of control and MMP inhibitor (100 μM NSC405020 + 20 μM prinomastat)-treated ES cells and XEN cells cultured in 2D. For ES cells, treatment started 48 h after 2i-LIF removal for 18 h as in b. XEN cells were treated with MMP inhibitors for 18 h. MMP inhibitor treatment does not induce cell death in 2D cell cultures. n = 3 independent experiments. g, Schematic showing the method for quantification of vector-map angles during embryo growth. h, Representative example of an E5.75 embryo showing a vector map following the direction of perforations in the epiblast. n = 10 embryos. i, Quantification of vector angles presented as a frequency plot; each 15° bin includes points of relative frequencies from 10 embryos. The same data are presented as a circular histogram in Fig. 4d. Kolmogorov–Smirnov test; ****P < 0.0001. Centre lines show median values and box limits represent the maximum and minimum values. Scale bars, 20 μm.
Extended Data Fig. 9 Posterior localization of basement membrane perforations and MMP14 expression in pre-gastrula and gastrula stages.
a, Representative examples of early-gastrula embryos showing posterior expression of MMP14. n = 15 embryos. b, En face posterior view of early-gastrula embryo. n = 10 embryos. In a, b, MMP14 expression follows the pattern of basement membrane perforations. White arrowheads, posterior and prospective primitive streak; purple arrowheads, breached basement membrane–primitive streak. c, Representative examples of E6.0–E6.5 embryos showing the pattern of basement membrane perforations in pre-gastrula stages. Basement membrane perforations pre-pattern the primitive streak in pre-gastrula stages. n = 30 embryos. d, En face posterior and anterior views of pre-gastrula embryos showing that basement membrane perforations are found only at the posterior side of the embryo. n = 10 embryos. Scale bars, 20 μm.
Extended Data Fig. 10 MMP-mediated basement membrane remodelling regulates primitive-streak extension.
a, Posterior en face views of gastrula embryos. Purple arrowheads, primitive streak (PS); white arrowheads, perforations. Right, depth-coded view. Epiblast basement membrane, cyan; endoderm basement membrane, white–red. n = 10 embryos. Scale bars, 50 μm. b, Representative examples of gastrula-stage embryos showing the pattern of basement membrane perforation in correlation with T (encoding Brachyury) expression (nuclear localization, halo around the embryo is due to background staining). White arrowheads, prospective primitive streak. Purple arrowheads, breached basement membrane–primitive streak. n = 20 embryos. Scale bars, 20 μm. c, Representative examples of embryos cultured (for 18 h) from early E6.5 (pre-primitive streak stage); n = 11 control and 17 MMP inhibitor-treated embryos. Scale bars: 50 μm (left), 80 μm (right; Supplementary Videos 8, 9). d, Surface-rendered images of embryos cultured from early E6.5 (for 18 h). Foxa2 is an anterior primitive streak (APS) marker. Ingressed (white arrows) and non-ingressed (white arrowheads) Foxa2-expressing cells. APS, magenta dotted line; primitive streak, purple dotted line. n = 10 control and 10 MMP inhibitor-treated embryos. Scale bars, 80 μm (main images); 20 μm (enlarged area). e, Schematic representation of primitive-streak extension along the perforation path and interpretation of primitive-streak appearance after inhibition of MMPs (NSC405020 + prinomastat) just before gastrulation.
Western blot gels for MMP2 and MMP14. Green boxes indicate bands shown in Extended data Figure 5D and Extended data Figure 6C. Red boxes indicate bands used additionally to quantify relative protein levels.
3D reconstruction of the basement membrane of embryos from E5.25 to E6.25, showing perforations distribution and re-distribution to one side upon entering the pre-gastrula stages (E6.25).
3D reconstruction of basement membrane(cyan) of embryos at different stages of AVE (marked by Cerberus, yellow) migration showing the localisation of basement membrane perforations at the posterior side of the embryo when AVE is migrated.
360o 3D reconstruction of the basement membrane surrounding the epiblast of an E6.5 pre-gastrula embryo showing the localisation of basement membrane perforations at the embryo’s posterior side.
360o 3D reconstruction of the basement membrane of the same embryo shown in Video 3. Here the basement membrane is presented from the internal side of the epilast.
Time lapse video of representative control (n=20) (left) and MMP inhibitors treated (n=18) (right) E5.75 embryos showing egg-cylinder expansion during post-implantation development. Time interval=30 min.
Time lapse video of representative control(n=20) (left) and MMP inhibitors treated (n=18) (right) 5 Lifeact-GFP transgenic E5.75 embryos showing egg-cylinder expansion during post-implantation development. Time interval=30 min.
3D reconstruction of basement membrane(cyan) combined with T expression of a representative E6.5 embryo.
3D reconstruction of control embryo imaged from the posterior (primitive streak en face) after culture from early E6.5 (prior to gastrulation initiation) for 18 hours. T-positive cells that successfully ingressed were automatically and manually spotted. The spots were then colour-coded based on their positions to distinguish between axial mesoderm (red), mesoderm wings (purple) and extraembryonic mesoderm (yellow). Stills from this reconstruction are shown in Extended Data Figure 10C.
3D reconstruction of embryo after culture from early E6.5 (prior to gastrulation initation) for 18 hours in the presence of MMP inhibitors NSC405020 and Prinomastat. T-positive cells were automatically and manually spotted. Spots were then colour-coded based on whether they remained trapped under the basement membrane (grey) or successfully ingressed (red). Stills from this reconstruction are shown in Extended Data Figure 10C.
T-GFP embryos cultured in the absence (embryo on the left) or presence of MMPs inhibitors NSC405020 and Prinomastat (two embryos on the right). Note that control embryo normally gastrulates and T-GFP cells are able to enter the mesoderm layer and primitive streak extends. Treated embryos on the other hand T-GFP cells remain proximally with no evidence of extending the primitive streak. n=3 control and 3 MMPs inhibitor treated embryos.
3D reconstruction of embryos cultured in the absence (left) or presence of MMPs inhibitors NSC405020 and Prinomastat for 18 hours from early E6.5. Cyan = surface-rendered perlecan. red = Foxa2, grey = T. Stills from this reconstruction are shown in Extended Data Figure 10D.
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Kyprianou, C., Christodoulou, N., Hamilton, R.S. et al. Basement membrane remodelling regulates mouse embryogenesis. Nature 582, 253–258 (2020). https://doi.org/10.1038/s41586-020-2264-2
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