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

Autor: Strasser AS; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA., Gonzalez-Reiche AS; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA., Zhou X; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA.; Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA., Valdebenito-Maturana B; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA., Ye X; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA., Zhang B; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA.; Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA.; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA., Wu M; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA. wu.meng@mayo.edu.; Department of Clinical Genomics, Mayo Clinic, 200 First Street, Rochester, MN, USA. wu.meng@mayo.edu.; Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street, Rochester, MN, USA. wu.meng@mayo.edu., van Bakel H; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA. harm.vanbakel@mssm.edu.; Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA. harm.vanbakel@mssm.edu.; Department of Microbiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA. harm.vanbakel@mssm.edu.; Department of Artificial Intelligence and Human Health, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA. harm.vanbakel@mssm.edu., Jabs EW; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA. jabs.ethylin@mayo.edu.; Department of Clinical Genomics, Mayo Clinic, 200 First Street, Rochester, MN, USA. jabs.ethylin@mayo.edu.; Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street, Rochester, MN, USA. jabs.ethylin@mayo.edu.; Department of Cell, Development and Regenerative Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA. jabs.ethylin@mayo.edu.; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA. jabs.ethylin@mayo.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Aug 21; Vol. 15 (1), pp. 7154. Date of Electronic Publication: 2024 Aug 21.
DOI: 10.1038/s41467-024-51328-3
Abstrakt: 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-Cre Tg/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).)
Databáze: MEDLINE
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