Mutation of LRP1 in cardiac neural crest cells causes congenital heart defects by perturbing outflow lengthening
| Autor: | Anupma Jha, Taylor Ridge, Angelo B. Arrigo, Grace Rong, Timothy N. Feinstein, Cecilia W. Lo, Jiuann-Huey I. Lin, Lindsey M. Maclay, Xinxiu Xu, Juan Xu, Jacob T. McCleary |
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| Rok vydání: | 2020 |
| Předmět: |
Heart Defects
Congenital 0301 basic medicine Embryology Mutation Missense Medicine (miscellaneous) Mice Transgenic 030204 cardiovascular system & hematology Biology Article General Biochemistry Genetics and Molecular Biology Focal adhesion 03 medical and health sciences 0302 clinical medicine Cell Movement Double outlet right ventricle medicine Animals Missense mutation Cell Lineage lcsh:QH301-705.5 Mice Knockout Disease model Cardiac neural crest cells Heart Septal Defects Myocardium Wnt signaling pathway Gene Expression Regulation Developmental Heart Cell migration medicine.disease LRP1 Cell biology Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure lcsh:Biology (General) Neural Crest embryonic structures Female Signal transduction General Agricultural and Biological Sciences Low Density Lipoprotein Receptor-Related Protein-1 |
| Zdroj: | Communications Biology, Vol 3, Iss 1, Pp 1-12 (2020) Communications Biology |
| ISSN: | 2399-3642 |
| DOI: | 10.1038/s42003-020-1035-9 |
| Popis: | 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. Lin et al. find that mutation in endocytic trafficking protein Lrp1 causes congenital heart defects in mice due to a requirement for Lrp1 in the neural crest lineage, where it regulates outflow tract lengthening. This study provides insights into how Lrp1 and the neural crest contribute to heart development. |
| Databáze: | OpenAIRE |
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