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Placentation defects are highly prevalent in embryonic lethal mouse mutants

Abstract

Large-scale phenotyping efforts have demonstrated that approximately 25–30% of mouse gene knockouts cause intrauterine lethality. Analysis of these mutants has largely focused on the embryo and not the placenta, despite the crucial role of this extraembryonic organ for developmental progression. Here we screened 103 embryonic lethal and sub-viable mouse knockout lines from the Deciphering the Mechanisms of Developmental Disorders program for placental phenotypes. We found that 68% of knockout lines that are lethal at or after mid-gestation exhibited placental dysmorphologies. Early lethality (embryonic days 9.5–14.5) is almost always associated with severe placental malformations. Placental defects correlate strongly with abnormal brain, heart and vascular development. Analysis of mutant trophoblast stem cells and conditional knockouts suggests that a considerable number of factors that cause embryonic lethality when ablated have primary gene function in trophoblast cells. Our data highlight the hugely under-appreciated importance of placental defects in contributing to abnormal embryo development and suggest key molecular nodes that govern placenta formation.

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Figure 1: Placental defects are highly prevalent in gene mutants that affect embryonic viability.
Figure 2: Summary of common placental defects and functional networks.
Figure 3: Phenotype co-associations between embryo and placenta.
Figure 4: Determining trophoblast-specific gene function.
Figure 5: Dissecting lineage origins of placental phenotypes.

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Acknowledgements

We would like to thank N. Karp for expert advice on statistical analyses, I. Sealy for help with PCA analyses, the Flow Cytometry Facility at the Babraham Institute, as well as all contributors to the DMDD programme. This work was supported by Wellcome Trust Strategic Award WT100160MA.

Author information

Authors and Affiliations

Authors

Contributions

V.P.-G., E.F., A.M., A.S. and M.H. performed the core experiments including histological analyses and TSC work; R.W. performed statistical co-association analyses and DMDD webpage data handling; C.I.M., C.T., J.K.W., E.T., E.J.R., D.G., E.S., H.W.-J. and A.G. performed all mouse colony management, breeding, sample collection and genotyping work; N.S., N.W., J.C. and E.M.B.-N. performed transcriptomics analyses; S.G., W.J.W. and T.M. performed HREM imaging and analyses, J.C.S, E.J.R., D.J.A., T.M. and M.H. designed the study, interpreted results and wrote the manuscript.

Corresponding author

Correspondence to Myriam Hemberger.

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The authors declare no competing financial interests.

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Reviewer Information Nature thanks J. Cross, E. Lacy and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Extended data figures and tables

Extended Data Figure 1 Potential trophoblast gene function in mutants with placental defect.

a, Expression of trophoblast control genes and the 103 DMDD genes in TSCs, TSCs differentiated for 1 or 3 days (d), and in E11.5 placentas. log2-transformed expression values (read counts per million) of RNA-seq data are displayed. Note that all genes associated with a placental phenotype in mutants (labelled in red font) are expressed in trophoblast. b, Frequency of placental defects annotated in mid-gestational lethal mutants (MP: 0011098) as annotated in the MGI database, compared to the findings in DMDD in which 40 out of 41 E9.5–E14.5 embryonic lethal mice were found to exhibit placental abnormalities. c, Left, volume rendered 3D model of the surface of a wild-type embryo, staged as Theiler stage (TS) 23, and coronal section through the volume rendered model. Right, equivalent images of a littermate E14.5 H13−/− embryo, staged as TS21. Note that the models are displayed in identical resolutions. Scale bar, 1 mm. Images are representative of at least five embryos per genotype. d, Network analysis using esyN (http://www.esyn.org) for all DMDD genes identified as causing a placental phenotype in mutants. BAP1 and ASXL3 are known interactors in humans. Red circles identify genes implicated in human trophoblast-based pathologies. The analysis reveals molecular nodes that appear to be of key importance for placental development.

Source data

Extended Data Figure 2 Identification of placental defects by haematoxylin and eosin histology.

a, Schematic representation of key stages and cell types in extraembryonic development, complementing Fig. 2c, d. All, allantois; Ch, chorion; Epi, epiblast; ExE, extraembryonic ectoderm; PE, primitive endoderm; SynT-I and SynT-II, syncytiotrophoblast layers I and II; TE, trophectoderm; VE, visceral endoderm. b, Examples of E9.5 placental phenotypes. Dotted lines denote the boundary to maternal decidua; vertical bars denote chorion trophoblast thickness; arrows in the wild-type placenta indicate invagination sites of extraembryonic mesoderm-derived blood vessels into chorionic trophoblast; arrowheads in the Psph−/− placenta denote sites of chorion folding but missing blood vessels; arrowheads in the Dpm1−/− placenta denote overabundant and enlarged trophoblast giant cells. c, Examples of E14.5 placental phenotypes. Red arrows indicate abnormal maternal blood accumulations. Arrows in Traf2−/− and Col4a3bp−/− (including inset) placentas denote fibrotic and/or necrotic areas; arrowheads in Chtop−/− and Pth1r−/− placentas indicate abnormal spongiotrophoblast inclusions. Representative mutant embryo images are also depicted. Images of mutant placentas in b and c are representative of at least three independent mutants per line, see Methods.

Extended Data Figure 3 Co-association analysis between embryo and placenta phenotypes.

a, Mutant mouse lines were classified into those that exhibit a placental phenotype at E14.5 and those that do not. All embryos analysed by HREM imaging were tagged accordingly to either of these two groups. Enrichment of embryonic phenotype terms in mutant strains with normal or abnormal placentas is shown (dark red denotes fully penetrant phenotype). For brevity, the ‘abnormal’ description has been removed from ontology terms. b, Significantly enriched embryonic phenotype terms in lines that exhibit an abnormal placenta (see also Supplementary Table 2) versus those with normal placenta. Following hypothesis testing using Fisher’s exact test, adjusting for multiple testing using the Benjamini–Hochberg method, we estimated the magnitude of the abnormal placenta effect. This was determined by calculating independent binomial proportions for the two groups of embryos with normal (n = 172) and abnormal (n = 69) placenta. The percentage difference between groups and the P values are shown.

Extended Data Figure 4 Specific embryonic defects are significantly correlated with the occurrence of an abnormal placenta.

a, Further, detailed co-association statistics between the occurrence of a placental phenotype and specific abnormalities in the embryo proper in DMDD lines. As before, mutant mouse lines were classified into those that exhibit a placental phenotype at E14.5 and those that do not. All embryos analysed by HREM imaging were tagged accordingly to either of these two groups. Significant differences in the frequency of specific embryonic defects was determined between these two groups, and scored for the size of the effect and for its significance. Following hypothesis testing using Fisher’s exact test, adjusting for multiple testing using the Benjamini–Hochberg method, we estimated the magnitude of the abnormal placenta effect. This was determined by calculating independent binomial proportions for the two groups of embryos with normal (n = 172) and abnormal (n = 69) placenta. The figure shows the differences in the estimated abnormality rates of the two embryo groups, and the extent of the bars represent the 95% Newcombe confidence interval (see Methods). ‘True’ means that these associations are significant, ‘false’ that they fall below the significance threshold. Please note that some terms, such as eye development and growth/size/body region, are probably a consequence of developmental retardation. However, the highlighted terms such as heart, brain and vascular system morphology are definitely based on abnormalities that are not merely due to developmental delay. b, Same analysis as in a but only including those specific embryos whose placentas that were analysed histologically (as opposed to all embryos per strain; n = 81 and n = 41 embryos having normal and abnormal placenta, respectively). Note that the important and meaningful terms hold up to significance irrespectively. c, HREM image of an example of a massive subcutaneous oedema (asterisk) covering the entire back of a Psph−/− embryo. Volume rendered 3D model. Axial section through the level of the heart is shown as inlay. Note also the delay in developmental progress. d, Muscular ventricular septal defect (arrowhead) in an Atp11a−/− embryo. Coronal section through volume rendered 3D model. Axial HREM image is shown as inlay. la, left atrial appendix; lv, left ventricle; pt, pulmonary trunk; ra, right atrial appendix; rv, right ventricle; vs, ventricular septum. Embryo defects shown in c and d are representative of at least three independent mutants.

Extended Data Figure 5 Major routes of TSC differentiation.

Diagram of the main differentiation routes of TSCs, including representative cell type-specific marker genes.

Extended Data Figure 6 Selection of genes for in-depth analysis of trophoblast contribution to embryonic lethality.

a, E9.5 phenotypes of mutant placentas of the three genes (Nubpl, Bap1 and Crb2) chosen for ablation in TSCs, as well as for placental rescue analysis in vivo (Fig. 5, Extended Data Figs 8, 9, 10). Black arrows (wild-type placenta) denote fetal blood vessels penetrating into the chorionic ectoderm. Vertical bars denote unpatterned appearance of chorion. Orange arrows indicate empty or fibrotic maternal blood spaces. Images are representative of at least three mutants per line. b, Details of CRISPR design and TSC clone screening strategy for the three selected genes Nubpl, Bap1 and Crb2. All targeted exons were first confirmed to be expressed in trophoblast. RT–qPCR (performed in technical triplicate per clone) and genomic genotyping PCR analysis (performed in duplicate per sample, with results independently confirmed by RT–qPCR data) were performed on individual, single-cell expanded TSC clones to confirm homozygous knockout. Of note, even though splicing may occur across the deleted exon, all CRISPR–Cas9 deletions were designed to result in a premature stop codon. RT–qPCR data are mean ± s.e.m. of n = 3 technical replicates.

Source data

Source data

Extended Data Figure 7 Analysis of mutant TSCs for defects in TSC maintenance and differentiation.

a, Nubpl−/− TSC clones assessed for additional trophoblast marker genes by RT–qPCR. b, Additional marker gene analysis on Bap1-mutant TSCs. c, Analysis of Crb2−/− TSC clones for a phenotype in stem-cell maintenance (0 days) or during differentiation (3 or 6 days). No significant difference in cell morphology, growth behaviour and gene expression pattern was observed compared to wild-type vector control clones. Data are mean ± s.e.m. *P < 0.05; **P < 0.01 (ANOVA with Holm–Bonferroni’s post-hoc test).

Source data

Extended Data Figure 8 Placental rescue of Sox2-cre-mediated conditional knockout of Nubpl.

a, Additional images of Nubpl-mutant embryos showing that a wild-type trophoblast compartment rescues the developmental retardation phenotype and embryonic defects observed in the full knockout at E9.5. At E11.5, Nubpl−/− embryos can still be recovered, whereas complete knockout embryos are not retrievable any more. Images are representative of at least ten independent embryos with the corresponding genotype. b, Histological analysis of the corresponding placentas at E11.5 shows a complete rescue of the placental defect in conditional knockouts with a genetically functional trophoblast lineage. Sections were stained for MCT4 (a SynT-II marker), E-cadherin (a global SynT marker) and laminin (blood vessel basement membrane marker). Images are representative of three placentas per genotype.

Extended Data Figure 9 Transcriptomic analysis of placentas from rescue experiments and developmental performance of Bap1 conditional knockouts.

a, Principal component analysis of global transcriptomes of E9.5 placentas with the indicated genotype. ‘Res’ refers to placentas from Sox2-cre-mediated conditional knockouts in which the trophoblast lineage remains functional, whereas the embryo is ablated for the gene of interest (E: KO; T: HET). b, Top, E9.5 embryo photos of the depicted genotypes for the Bap1 strain. The embryonic lethality of the complete Bap1 knockout cannot be rescued by a functional trophoblast compartment. Images are representative of at least 12 independent embryos per genotype. Bottom, histological analysis of the corresponding placentas, stained as in Fig. 5b and Extended Data Fig. 8b. Arrows point to partially rescued syncytiotrophoblast loops and some vascular invaginations into the chorionic ectoderm. Yet the vascularisation of the forming labyrinth layer remains under-developed compared to controls. Images are representative of three placentas per genotype.

Extended Data Figure 10 Analysis of yolk sac morphology in Nubpl, Bap1 and Crb2 mutants and developmental performance of Crb2 conditional knockout.

a, Immunofluorescence staining of yolk sacs for E-cadherin (green) and laminin (red) demarcating the visceral endoderm (VE) and basement membrane of the yolk sac mesoderm (YSM), respectively. Bl, blood cells. Bap1 and Crb2 mutants show a defect characterized by the lack of attachment of the two visceral yolk sac layers (arrows). This defect cannot be rescued by the Sox2-cre-mediated conditional knockout, indicating that its cause resides in the extra-embryonic mesoderm lineage. b, Developmental performance of Crb2 knockout and conditional knockout embryos and analysis of placental morphology, equivalent to Extended Data Figs 8b and 9b. No rescue of embryonic lethality or placental defects is observed in the conditional knockouts. Images are representative of at least three independent conceptuses per genotype.

Supplementary information

Life Sciences Reporting Summary (PDF 91 kb)

Supplementary Table 1

This file contains a summary of all mutant mouse lines analysed. (XLSX 56 kb)

Supplementary Table 2

This table contains phenotyping terms that are significantly enriched in mutant lines with placental defect. (XLSX 65 kb)

Supplementary Table 3

This table contains mouse phenotyping (MP) terms used for penetrance analysis. (XLSX 47 kb)

Supplementary Table 4

This table contains a list of primers and gRNAs. (PDF 749 kb)

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Perez-Garcia, V., Fineberg, E., Wilson, R. et al. Placentation defects are highly prevalent in embryonic lethal mouse mutants. Nature 555, 463–468 (2018). https://doi.org/10.1038/nature26002

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