1. Limb reduction in an Esco2 cohesinopathy mouse model is mediated by p53-dependent apoptosis and vascular disruption.
- Author
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Strasser AS, Gonzalez-Reiche AS, Zhou X, Valdebenito-Maturana B, Ye X, Zhang B, Wu M, van Bakel H, and Jabs EW
- Subjects
- Animals, Mice, Cell Cycle Proteins metabolism, Cell Cycle Proteins genetics, Female, Toluene analogs & derivatives, Toluene pharmacology, Ectromelia genetics, Ectromelia metabolism, Ectromelia pathology, Benzothiazoles pharmacology, Signal Transduction, Male, DNA Damage, Cell Cycle Checkpoints genetics, Cell Cycle Checkpoints drug effects, Limb Buds metabolism, Hemorrhage pathology, Hemorrhage genetics, Hypertelorism, Homeodomain Proteins, Craniofacial Abnormalities, Tumor Suppressor Protein p53 metabolism, Tumor Suppressor Protein p53 genetics, Apoptosis genetics, Disease Models, Animal, Cohesins, Chromosomal Proteins, Non-Histone metabolism, Chromosomal Proteins, Non-Histone genetics, Limb Deformities, Congenital genetics, Limb Deformities, Congenital pathology, Limb Deformities, Congenital metabolism
- 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 Esco2
fl/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., (© 2024. The Author(s).)- Published
- 2024
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