Limb reduction in an Esco2 cohesinopathy mouse model is mediated by p53-dependent apoptosis and vascular disruption.
Nat Commun
; 15(1): 7154, 2024 Aug 21.
Article
de En
| MEDLINE
| ID: mdl-39168984
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.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Protéines chromosomiques nonhistones
/
Protéine p53 suppresseur de tumeur
/
Apoptose
/
Anomalies morphologiques congénitales des membres
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Modèles animaux de maladie humaine
/
Cohesins
Limites:
Animals
Langue:
En
Journal:
Nat Commun
Sujet du journal:
BIOLOGIA
/
CIENCIA
Année:
2024
Type de document:
Article
Pays d'affiliation:
États-Unis d'Amérique
Pays de publication:
Royaume-Uni