Investigating the function of Creld1 in the heart in vivo and in vitro

• Applicant: Professorin Dr. Dagmar Wachten
• Subject Area: Developmental Biology ; Cardiology, Angiology ; Cell Biology
• Term: from 2014 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 266024333

Congenital heart defects are the most common type of birth defects. Atrioventricular septal defects (AVSD) constitute ca. 7% of all cardiac congenital malformations. Frequently, AVSD is associated with Down syndrome. We identified Creld1 (Cysteine-rich with EGF-like domains 1) as a new key player that regulates the formation of atrioventricular septa and, thereby, the development of a four-chambered heart. Global Creld1 knock-out mice (Creld1KO) die during embryonic development at E11.5, because the development of the cardiac valves and the separation of the chambers is impaired. Creld1 regulates heart development by controlling the activity of the most important signaling cascade during valve formation, the calcineurin/NFAT signaling-pathway. However, calcineurin-NFAT signaling in the heart controls different functions depending on the cell-type e.g. in endocardial or myocardial cells. Cell-specific functions of Creld1 are difficult to address in global Creld1KO mice. Thus, we will use conditional Creld1KO mice that lack Creld1 in the endocard or the myocard to unravel cell-type specific functions of Creld1 during heart development. Mutations in the human CRELD1 gene have been linked with the development of AVSD, in particular in Down syndrome patients. To reveal whether mutations in CRELD1 indeed contribute to the development of AVSD and how this is linked to Down syndrome, we will generate Creld1 knock-in mice carrying the corresponding mutations from human patients in the mouse Creld1 gene. Knock-in mice will also be analyzed in a Down syndrome model to study the link between Creld1 and the development of AVSD in Down syndrome.Our data indicate that Creld1-dependent activation of the calcineurin/NFATc1 signaling is controlled by VEGF. However, how VEGF acts on Creld1 is not known. The majority of VEGF-dependent cellular responses are mediated via the VEGF receptor VEGFR2. Thus, we will analyze VEGFR2/Creld/calcineurin/NFAT signaling using pharmacological tools in mouse embryonic fibroblast from wild-type and Creld1KO mice. Taken together, the results from this study will provide a deeper understanding of the role of Creld1 in the development of AVSD in vivo and in vitro.

• DFG Programme: Research Grants