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

Arielle S. Strasser, Ana Silvia Gonzalez-Reiche, Xianxiao Zhou, Braulio Valdebenito-Maturana, Xiaoqian Ye, Bin Zhang, Meng Wu (), Harm Bakel () and Ethylin Wang Jabs ()
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Arielle S. Strasser: One Gustave L. Levy Place
Ana Silvia Gonzalez-Reiche: One Gustave L. Levy Place
Xianxiao Zhou: 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
Meng Wu: One Gustave L. Levy Place
Harm Bakel: One Gustave L. Levy Place
Ethylin Wang Jabs: One Gustave L. Levy Place

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51328-3

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