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Limb reduction in an Esco2 cohesinopathy mouse model is mediated by p53-dependent apoptosis and vascular disruption

Author

Listed:
  • Arielle S. Strasser

    (One Gustave L. Levy Place)

  • Ana Silvia Gonzalez-Reiche

    (One Gustave L. Levy Place)

  • Xianxiao Zhou

    (One Gustave L. Levy Place
    One Gustave L. Levy Place)

  • Braulio Valdebenito-Maturana

    (One Gustave L. Levy Place)

  • Xiaoqian Ye

    (One Gustave L. Levy Place)

  • Bin Zhang

    (One Gustave L. Levy Place
    One Gustave L. Levy Place
    One Gustave L. Levy Place)

  • Meng Wu

    (One Gustave L. Levy Place
    Mayo Clinic
    Mayo Clinic)

  • Harm Bakel

    (One Gustave L. Levy Place
    One Gustave L. Levy Place
    One Gustave L. Levy Place
    One Gustave L. Levy Place)

  • Ethylin Wang Jabs

    (One Gustave L. Levy Place
    Mayo Clinic
    Mayo Clinic
    One Gustave L. Levy Place)

Abstract

Roberts syndrome (RBS) is an autosomal recessive disorder with profound growth deficiency and limb reduction caused by ESCO2 loss-of-function variants. Here, we elucidate the pathogenesis of limb reduction in an Esco2fl/fl;Prrx1-CreTg/0 mouse model using bulk- and single-cell-RNA-seq and gene co-expression network analyses during embryogenesis. Our results reveal morphological and vascular defects culminating in hemorrhage of mutant limbs at E12.5. Underlying this abnormal developmental progression is a pre-apoptotic, mesenchymal cell population specific to mutant limb buds enriched for p53-related signaling beginning at E9.5. We then characterize these p53-related processes of cell cycle arrest, DNA damage, cell death, and the inflammatory leukotriene signaling pathway in vivo. In utero treatment with pifithrin-α, a p53 inhibitor, rescued the hemorrhage in mutant limbs. Lastly, significant enrichments were identified among genes associated with RBS, thalidomide embryopathy, and other genetic limb reduction disorders, suggesting a common vascular etiology among these conditions.

Suggested Citation

  • Arielle S. Strasser & Ana Silvia Gonzalez-Reiche & Xianxiao Zhou & Braulio Valdebenito-Maturana & Xiaoqian Ye & Bin Zhang & Meng Wu & Harm Bakel & Ethylin Wang Jabs, 2024. "Limb reduction in an Esco2 cohesinopathy mouse model is mediated by p53-dependent apoptosis and vascular disruption," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51328-3
    DOI: 10.1038/s41467-024-51328-3
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    References listed on IDEAS

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    1. Gioele La Manno & Ruslan Soldatov & Amit Zeisel & Emelie Braun & Hannah Hochgerner & Viktor Petukhov & Katja Lidschreiber & Maria E. Kastriti & Peter Lönnerberg & Alessandro Furlan & Jean Fan & Lars E, 2018. "RNA velocity of single cells," Nature, Nature, vol. 560(7719), pages 494-498, August.
    2. Kornelia Polyak & Yong Xia & Jay L. Zweier & Kenneth W. Kinzler & Bert Vogelstein, 1997. "A model for p53-induced apoptosis," Nature, Nature, vol. 389(6648), pages 300-305, September.
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