Mutation of LRP1 in cardiac neural crest cells causes congenital heart defects by perturbing outflow lengthening.
Commun Biol
; 3(1): 312, 2020 06 16.
Article
in En
| MEDLINE
| ID: mdl-32546759
ABSTRACT
The recent recovery of mutations in vesicular trafficking genes causing congenital heart disease (CHD) revealed an unexpected role for the endocytic pathway. We now show that mice with a C4232R missense mutation in Low density lipoprotein receptor related protein 1 (LRP1) exhibit atrioventricular septal defects with double outlet right ventricle. Lrp1m/m mice exhibit shortened outflow tracts (OFT) and dysmorphic hypocellular cushions with reduced proliferation and increased apoptosis. Lrp1m/m embryonic fibroblasts show decreased cell motility and focal adhesion turnover associated with retention of mutant LRP1 in endoplasmic reticulum and reduced LRP1 expression. Conditional deletion of Lrp1 in cardiac neural crest cells (CNC) replicates the full CHD phenotype. Cushion explants showed defective cell migration, with gene expression analysis indicating perturbation of Wnt and other signaling pathways. Thus, LRP1 function in CNCs is required for normal OFT development with other cell lineages along the CNC migratory path playing a supporting role.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Mutation, Missense
/
Low Density Lipoprotein Receptor-Related Protein-1
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Heart
/
Heart Defects, Congenital
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Neural Crest
Type of study:
Etiology_studies
Limits:
Animals
Language:
En
Journal:
Commun Biol
Year:
2020
Document type:
Article
Affiliation country:
United States
Country of publication:
ENGLAND
/
ESCOCIA
/
GB
/
GREAT BRITAIN
/
INGLATERRA
/
REINO UNIDO
/
SCOTLAND
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UK
/
UNITED KINGDOM