Placentation defects are highly prevalent in embryonic lethal mouse mutants

Pérez-García, Vicente; Fineberg, Elena; Wilson, Robert; Murray, Alexander; Mazzeo, Cecilia Icoresi; Tudor, Catherine; Sienerth, Arnold R.; White, Jacqueline K.; Tuck, Elizabeth; Ryder, Edward; Gleeson, Diane; Siragher, Emma; Wardle‐Jones, Hannah; Staudt, Nicole; Wali, Neha; Collins, John; Geyer, Stefan H.; Busch-Nentwich, Elisabeth M; Galli, Antonella; Smith, James C.; Robertson, Elizabeth J.; Adams, David J.; Weninger, Wolfgang J.; Mohun, Timothy J.; Hemberger, Myriam

doi:10.1038/nature26002

Cited by 301 publications

(310 citation statements)

References 48 publications

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“…Additional skeletal consequences of gene deletion were investigated by: (i) identifying whether mutant mice had abnormalities of bone structure and strength 16 , (ii) IMPC IMPReSS phenotype screening, (iii) analysis of the skeleton in embryos from lines in which homozygous gene deletion was lethal or resulted in sub-viability 25 , and (iv) determining whether mutations of the same gene had skeletal abnormalities identified in Mouse Genome Informatics (MGI) databases or the published literature. The top ranked genes with major effects on skeletal phenotype were Pitx1, basic helix-loop-helix family member e40 (Bhlhe40), SR-related CTD associated factor 11 (Scaf11) and SMG9 nonsense mediated mRNA decay factor (Smg9) ( Figure 1, Supplementary Table 6).…”

Section: Prioritization Of 25 Mouse Mutants With Outlier Joint Phenotmentioning

confidence: 99%

Accelerating functional gene discovery in osteoarthritis

Butterfield

Curry

Steinberg

et al. 2019

Preprint

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Osteoarthritis causes debilitating pain and disability, resulting in a huge socioeconomic burden, yet no drugs are available that prevent disease onset or progression. Here, we develop, validate and use rapid-throughput imaging techniques to identify abnormal joint phenotypes in unselected mutant mice generated by the International Knockout Mouse Consortium. We identify 14 genes with functional involvement in osteoarthritis pathogenesis, including the homeobox gene Pitx1, and functionally characterize 6 candidate human osteoarthritis genes in mouse models. We demonstrate sensitivity of the methods by identifying age-related degenerative joint damage in wild-type mice. Finally, we generate mutant mice with an osteoarthritis-associated polymorphism in the Dio2 gene by Crispr/Cas9 genome editing and demonstrate a protective role in disease onset with public health implications. This expanding resource of unselected mutant mice will transform the field by accelerating functional gene discovery in osteoarthritis and offering unanticipated drug discovery opportunities for this common and incapacitating chronic disease.

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Section: Prioritization Of 25 Mouse Mutants With Outlier Joint Phenotmentioning

confidence: 99%

Accelerating functional gene discovery in osteoarthritis

Butterfield

Curry

Steinberg

et al. 2019

Preprint

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“…Placentation defects such as these have recently been identified as a leading cause of embryonic lethality in mouse mutants (26). In their study of 82 mouse lines which were classified as P14 lethal but where embryos could be recovered at either E9.5 or E14.5, 68% were found to have aberrant placental morphology.…”

Section: Discussionmentioning

confidence: 99%

“…The placenta was isolated from embryos at E10.5 and examined as reported previously (26). Briefly, placentas were fixed in 4% paraformaldehyde and processed for paraffin embedding following standard procedures.…”

Section: Mouse Placental Histologymentioning

confidence: 99%

Diverse Species-Specific Phenotypic Consequences of Loss of Function Sorting Nexin 14 Mutations

Bryant¹,

Seda²,

Peskett³

et al. 2019

Preprint

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Mutations in the SNX14 gene cause spinocerebellar ataxia, autosomal recessive 20 (SCAR20) in both humans and dogs. SCAR20 is understood to involve subcellular disruption to autophagy and lipid metabolism. Previously reported studies on the phenotypic consequences of SNX14 mutations have been limited to in vitro investigation of patient-derived dermal fibroblasts, laboratory engineered cell lines and developmental analysis of zebrafish morphants. In addition, studies have investigated the biochemical roles of SNX14 homologues Snz (Drosophila) andMdm1 (yeast) which have demonstrated an important role during lipid biogenesis.This study investigates the impact of constitutive Snx14 mutations in laboratory species: mice and zebrafish. Loss of SNX14 in mice was found to be embryonic lethal around mid-gestation. This is due to placental pathology that involves severe disruption to syncytiotrophoblast cell differentiation. Zebrafish carrying a homozygous, maternal zygotic snx14 genetic loss-of-function mutation contrasts with other vertebrates, being both viable and anatomically normal. Whilst no obvious behavioural effects were observed, elevated levels of neutral lipids and phospholipids resemble previously reported effects on lipid homeostasis in other species. The biochemical role of SNX14 therefore appears largely conserved through evolution while the overall consequences of loss of function varies considerably between species. New mouse and zebrafish models therefore provide valuable insights into the functional importance of SNX14 with distinct opportunities for investigating its cellular and metabolic function in vivo.

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“…In addition to the enlarged maternal blood sinuses, E-cadherin (Cdh1), a marker of syncytiotrophoblasts 36 , has markedly diminished expression in the TMEM16F -/labyrinth layer (Figures 4F(iii), 4G(iii) and S4A), suggesting that the TMEM16F KO placentas have defective syncytialization.…”

Section: Tmem16f Knockout Mice Exhibit Deficiency On Trophoblast Fusimentioning

confidence: 99%

TMEM16F phospholipid scramblase mediates trophoblast fusion and placental development

Zhang

Grabau

et al. 2019

Preprint

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AbstractCell-cell fusion or syncytialization is fundamental to the reproduction, development and homeostasis of multicellular organisms. In addition to various cell-type specific fusogenic proteins, cell surface externalization of phosphatidylserine (PS), a universal eat-me signal in apoptotic cells, has been observed in different cell-fusion events. Nevertheless, molecular underpinnings of PS externalization and cellular mechanisms of PS-facilitated cell-cell fusion are unclear. Here we report that TMEM16F, a Ca2+-activated phospholipid scramblase (CaPLSase), plays an indispensable role in placental trophoblast fusion by translocating PS to the cell surface independent of apoptosis. Consistent with its essential role in trophoblast fusion, the placentas from TMEM16F-deficient mice exhibit deficiency in syncytialization, placental developmental defects and perinatal lethality. Our findings thus identify a cell-cell fusion mechanism by which TMEM16F CaPLSase-dependent externalization of PS serves as a critical cell fusion signal to facilitate trophoblast syncytialization and placental development.

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Placentation defects are highly prevalent in embryonic lethal mouse mutants

Cited by 301 publications

References 48 publications

Accelerating functional gene discovery in osteoarthritis

Accelerating functional gene discovery in osteoarthritis

Diverse Species-Specific Phenotypic Consequences of Loss of Function Sorting Nexin 14 Mutations

TMEM16F phospholipid scramblase mediates trophoblast fusion and placental development

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