View Program - 63rd Annual Drosophila Research Conference

Congenital Heart Disease (CHD) is driven by a strong genetic predisposition, yet only a small subset of patients (~20%) are diagnosed with a precise genetic cause. Therefore, expanding the pool of genes associated with CHD and establishing the functional relationships between genes can assemble a more comprehensive genetic network to better understand cardiac development and pathogenesis. In our studies, we identified protein biogenesis cofactors Nascent polypeptide Associated Complex (NAC) and Signal Recognition Particle (SRP) that bind disparate subsets of emerging nascent polypeptides at the ribosome exit site to direct polypeptide fates, as novel regulators of cell differentiation and cardiac morphogenesis. Knockdown (KD) of the α- (Nacα) or β- subunit (bicaudal) of NAC in the developing Drosophila heart led to disruption of cardiac remodeling during pupal stages resulting in an adult fly with no heart. Heart loss was rescued by combined KD of Nacα with the hox gene abd-B. This genetic interaction between hox genes and Nacα was recapitulated in differentiation assays using human Multipotent Cardiac Progenitors (MCPs). KD of Nacα in MCPs led to decreased cardiomyocytes (CM) and increased fibroblasts (Fib) which were reversed upon co-KD with mammalian hox genes HOXC12 and HOXD12. KD of cardiogenic transcription factors (TFs) Gata4/6 and MyoCD led to different population growth profiles, with decreased CMs but no change in Fibs, indicating that Nacα may utilize distinct mechanisms in driving cell fates compared to these TFs. The effect of Nacα KD on the fly heart was temporally regulated, in that KD in embryo or in pupae caused only a partial loss of the heart, whereas KD during both stages led to heart loss similar to continuous KD throughout life. This suggests that embryonic Nacα KD may in part reprogram cells leading to aberrant cardiac remodeling during pupal stages. Lastly, KD of several SRP subunits individually in the fly heart produced a range of cardiac phenotypes that targeted specific segments and cell types, indicating spatially regulated activities of SRP components in the heart. Together, these data suggest that despite NAC and SRP ubiquitous presence, they displayed spatially and temporally fine-tuned activities for proper cardiac morphogenesis. Nacα’s interaction with cardiac-specific hox gene functions builds upon the novel role of this pathway and expands our understanding of the complex genetic networks involved in cardiac development and pathogenesis.

Protein biogenesis factors Nascent Polypeptide Associated Complex–alpha and Signal Recognition Particle are required in heart development

**Protein biogenesis factors Nascent Polypeptide Associated Complex–alpha and Signal Recognition Particle are required in heart development**