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- Title
Nascent polypeptide-Associated Complex and Signal Recognition Particle have cardiac-specific roles in heart development and remodeling.
- Authors
Schroeder, Analyne M.; Nielsen, Tanja; Lynott, Michaela; Vogler, Georg; Colas, Alexandre R.; Bodmer, Rolf
- Abstract
Establishing a catalog of Congenital Heart Disease (CHD) genes and identifying functional networks would improve our understanding of its oligogenic underpinnings. Our studies identified protein biogenesis cofactors Nascent polypeptide-Associated Complex (NAC) and Signal-Recognition-Particle (SRP) as disease candidates and novel regulators of cardiac differentiation and morphogenesis. Knockdown (KD) of the alpha- (Nacα) or beta-subunit (bicaudal, bic) of NAC in the developing Drosophila heart disrupted cardiac developmental remodeling resulting in a fly with no heart. Heart loss was rescued by combined KD of Nacα with the posterior patterning Hox gene Abd-B. Consistent with a central role for this interaction in cardiogenesis, KD of Nacα in cardiac progenitors derived from human iPSCs impaired cardiac differentiation while co-KD with human HOXC12 and HOXD12 rescued this phenotype. Our data suggest that Nacα KD preprograms cardioblasts in the embryo for abortive remodeling later during metamorphosis, as Nacα KD during translation-intensive larval growth or pupal remodeling only causes moderate heart defects. KD of SRP subunits in the developing fly heart produced phenotypes that targeted specific segments and cell types, again suggesting cardiac-specific and spatially regulated activities. Together, we demonstrated directed function for NAC and SRP in heart development, and that regulation of NAC function depends on Hox genes. Author summary: Identifying novel genes involved in cardiac development could help patients with Congenital Heart Disease through improved understanding of the developmental missteps, more precise patient diagnosis, and invention of targeted medical interventions. We identified protein biogenesis cofactors Nascent polypeptide Associated Complex (NAC) and Signal Recognition Peptide (SRP) to be involved in cardiac specific roles during development. Disruption of NAC and SRP subunits led to distinct and cell targeted disruptions in the heart, which would be unexpected if NAC and SRP merely had generic cellular function. Specifically, in flies, knockdown (KD) of the alpha- subunit of NAC, Nacα, led to an adult fly with no heart that could be rescued by co-KD with the posterior patterning Hox gene Abd-B, indicating a critical developmentally relevant genetic interaction, and not merely a generic protein biogenesis defect. This interaction was recapitulated in human Cardiac Progenitors, whereby human NACA KD redirected progenitor differentiation away from cardiomyocyte and toward fibroblast fates, which was rescued by concomitant Hox gene KD. Lastly, Nacα activity was required at specific times during development, and depending on when Nacα was knocked down, the resulting adult heart could be mildly or severely malformed. Thus, the work presents a new class of genes involved in protein biogenesis that display tissue- and temporal-specific activities that are crucial for proper heart development.
- Subjects
HEART development; CONGENITAL heart disease; HEART abnormalities; PEPTIDES; CARDIAC patients; MYOCARDIAL reperfusion; CHLOROPLAST formation
- Publication
PLoS Genetics, 2022, Vol 18, Issue 10, p1
- ISSN
1553-7390
- Publication type
Article
- DOI
10.1371/journal.pgen.1010448