Cardiac malformations are the most common congenital anomalies observed in humans, and the most frequently affected structures are the valves and septa of the heart. Furthermore, the incidence of valvuloseptal abnormalities is significantly higher in individuals with Down syndrome relative to the general population. Therefore, identifying the molecular mechanisms of heart valve and septal formation and the Down syndrome candidate genes that contribute to this developmental process has significant clinical relevance. Signaling through the protein phosphatase calcineurin and its transcriptional effector, nuclear factor of activated T-cells c1 (NFATc1), is essential for proper valvuloseptal development. However, the necessary activators of this pathway in the developing heart valves and the downstream targets that govern valve leaflet morphogenesis are poorly understood. The studies herein examine calcineurin/NFATc1 pathway function in the developing heart to gain insight into the molecular regulation of normal and abnormal valvulogenesis. The Down syndrome candidate gene Down syndrome critical region 1 (DSCR1) encodes a regulator of calcineurin/NFAT signaling that binds calcineurin and modulates its phosphatase activity. Gene expression analysis demonstrates that NFATc1 regulates a splice variant of DSCR1 in the developing heart valves through a conserved intragenic promoter element. Examination of DSCR1 expression in the trisomy 16 (Ts16) murine model of Down syndrome reveals that it is present in the abnormally developing organ structures associated with human trisomy 21 phenotypes. Further, the developing hearts and brains of Ts16 embryos have elevated expression of DSCR1 and reduced NFAT transcriptional activity, indicating that aberrant levels of DSCR1 may contribute to Down syndrome phenotypes through disruption of normal calcineurin/NFAT signaling. However, specific restoration of DSCR1 to disomic levels in Ts16 embryos does not correct Down syndrome-related developmental anomalies. Additional analyses of valve leaflet formation reveal that NFATc1 expression in the developing valves colocalizes with and is responsive to the receptor activator of NFκB ligand (RANKL) pathway. Further, NFATc1 is required for expression of the extracellular matrix protease cathepsin K in the remodeling valve leaflets. Altogether, these studies determine the individual contribution of DSCR1 to Down syndrome-related developmental abnormalities and advance the understanding of the molecular mechanisms that control heart valve leaflet morphogenesis.
|School:||University of Cincinnati|
|Department:||Medicine : Molecular and Developmental Biology|
|School Location:||United States -- Ohio|
|Source:||DAI-B 79/10(E), Dissertation Abstracts International|
|Keywords:||Down syndrome, Dscr1, Heart valve development, Nfatc1, Rankl, Trisomy 16 mice|
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