Abstract Body (Do not enter title and authors here): Background: Congenital heart defects (CHDs) are the most common birth defects globally and often require palliative surgical interventions with limited long-term effectiveness. Prenatal detection of CHDs is challenging due to the absence of heart failure signs in most fetuses. Thus, early detection methods and therapeutic drugs to correct abnormal heart development are crucial. We have discovered that the RNA-binding protein Bicaudal-C homolog 1 (Bicc1) influences normal and abnormal heart development. Bicc1 is involved in post-transcriptional regulation and interacts with RNA interference (RNAi) components. While its role in left-right patterning, kidney development, and the interaction with PKD genes (Pkd1 and Pkd2) is documented, the role of Bicc1 and its expression in heart development and whether it relies on interaction with Pkd1/Pkd2 are not understood.
Methods and Results: To start addressing these knowledge gaps, we used a transgenic mouse line with an in-frame fusion of Bicc1 and the LacZ reporter gene to perform β-galactosidase staining, RNAscope and immunostaining to identify the cardiac cell types expressing Bicc1. High Bicc1 expression was observed in embryonic and neonatal hearts, particularly in the ventricles, atria, and endothelial cells of blood vessels. Expression decreased in adulthood but persisted at basal levels. We observed that Bicc1 knockout (KO) developed heterotaxy of the heart and enlarged atria. Next, to elucidate the gene and miRNA regulatory networks involved in cardiac development disrupted by the absence of Bicc1, we carried out RNA- and miRNA-seq on hearts from wild-type and Bicc1 KO embryonic hearts at different developmental stages. Several genes and miRNAs associated with ciliopathy and heterotaxy, including miR-196, Hand1, and Lefy2, were significantly altered in Bicc1 KO mice. Moreover, as reported for the kidney, Pkd2 mRNA expression was altered in Bicc1 KO mice, while Pkd1 expression remained unchanged. Finally, we detected changes linked to lipid metabolism and related pathways, such as members of aldehyde dehydrogenase (Adlh1a) and cytochrome P450 family (Cyp5a1), that were altered in the absence of Bicc1.
Conclusions: Our study reveals additional role(s) for Bicc1 in heart development suggesting its involvement in regulating heart metabolism in fetuses. These findings provide a conceptual basis for future investigations into the function of Bicc1 in heart development and how its disruption contributes to CHDs.