Calcineurin/NFAT Signaling in Heart Development
Calcineurin/NFAT Signaling and Myocardial Maturation
Calcineurin signaling through NFAT activation regulates programmatic changes in contractile protein and metabolic gene expression in adult cardiac hypertrophy (See Jeff Molkentin's Lab page). Studies in mice and chicken embryos are designed to determine the functions of calcineurin signaling and NFAT activation in the developing heart. Gene targeting studies in mice demonstrated that NFATc3 and NFATc4 together are required for the metabolic maturation of the myocardium at midgestation. Similar defects in heart development were observed in chicken embryos treated with the calcineurin inhibitor, cyclosporin. Studies in progress are designed to identify NFAT target genes important for cardiac muscle maturation.
DSCR1 (also called MCIP1) is a calcineurin interacting protein present in the Down syndrome critical region of human chromosome 21. DSCR1 gene expression is regulated by NFATc1 during valve maturation and coincides with abnormal development in a mouse model of Down syndrome. Additional targets of NFATc1 in the developing valves include genes expressed in osteoclasts and indicate an important role for RANKL/NFAT signaling in heart valve remodeling.
Related Publications
Bushdid, PB, Osinska, H, Waclaw, RR, Molkentin, JD and Yutzey, KE (2003) NFATc3/NFATc4 are required for cardiac development and mitochondrial function. Circ. Res. 92:1305-1313 (cover article).
Schulz, RA and KE Yutzey (2004) Calcineurin signaling and NFAT activation in cardiovascular and skeletal muscle development. Dev. Biol. 266:1-16.
Lange AW, JD Molkentin, and KE Yutzey. (2004) DSCR1 gene expression is dependent on NFATc1 during cardiac valve formation and colocalizes with anomalous organ development in trisomy 16 mice. Dev. Biol. 266:346-360.
Liberatore, CM and KE Yutzey. (2004) Calcineurin signaling in avian cardiovascular development. Dev. Dynam. 229:300-311.
Parsons, SA, DP Millay, BJ Wilkins, OF Bueno, GL Tsika, JR Neilson, CM Liberatore, KE Yutzey, GR Crabtree, RW Tsika, JD Molkentin (2004) Genetic loss of calcineurin blocks mechanical overload-induced skeletal muscle fiber type switching but not hypertrophy. J. Biol. Chem. 279: 26192-26200.
Lange, AW, BA Rothermel, and KE Yutzey (2005). Restoration of DSCR1 to disomy in Trisomy 16 mice does not prevent Down syndrome-related cardiac or craniofacial development anomalies. Dev. Dynam. 233:954-963.
Lange, AW and KE Yutzey (2006). NFATc1 expression in the developing heart valves is responsive to the RANKL pathway and is required for endocardial expression of cathepsin K. Dev. Biol. In press.
Contact Katherine Yutzey
Katherine Yutzey, PhD
Division of Molecular Cardiovascular Biology
Cincinnati Children's Hosptial Medical Center
ML7020
3333 Burnet Avenue
Cincinnati, OH 45229
Phone 513-636-8340
Fax 513-636-5958
Email yutzey@cchmc.org
