| First Author | Kan-O M | Year | 2012 |
| Journal | Biol Open | Volume | 1 |
| Issue | 9 | Pages | 889-96 |
| PubMed ID | 23213483 | Mgi Jnum | J:187358 |
| Mgi Id | MGI:5436289 | Doi | 10.1242/bio.20121370 |
| Citation | Kan-o M, et al. (2012) Mammalian formin Fhod3 plays an essential role in cardiogenesis by organizing myofibrillogenesis. Biol Open 1(9):889-896 |
| abstractText | Heart development requires organized integration of actin filaments into the sarcomere, the contractile unit of myofibrils, although it remains largely unknown how actin filaments are assembled during myofibrillogenesis. Here we show that Fhod3, a member of the formin family of proteins that play pivotal roles in actin filament assembly, is essential for myofibrillogenesis at an early stage of heart development. Fhod32/2 mice appear normal up to embryonic day (E) 8.5, when the developing heart, composed of premyofibrils, initiates spontaneous contraction. However, these premyofibrils fail to mature and myocardial development does not continue, leading to embryonic lethality by E11.5. Transgenic expression of wild-type Fhod3 in the heart restores myofibril maturation and cardiomyogenesis, which Introduction The heart is the first organ to form and function during embryogenesis, and assures biological activities throughout the life by its contractile activity. Sufficient contraction of the developing heart requires maturation of myofibrils, composed of repeating units known as sarcomeres, where arrays of actin (thin) and myosin (thick) filaments comprise the contractile apparatus (Clark et al., 2002). In the sarcomere, barbed ends of actin filaments are anchored in the Z-line, and their pointed ends extend into the middle of the sarcomere. The initiation of the heartbeat occurs before sarcomere maturation (and thus before myofibril maturation), and is followed by myocardial development with trabeculation (formation of finger-like projections of the myocardium into the ventricular lumen) and by chamber formation, which begins with looping of the heart tube (Moorman and Christoffels, 2003; Taber, 1998). The molecular mechanisms by which the sarcomere is organized during cardiogenesis remain poorly understood. During sarcomere organization in the striated muscle (i.e., the skeletal and cardiac muscles), actin cytoskeleton undergoes dynamic rearrangement to form mature actin filaments with uniform length and polarity (Gregorio and Antin, 2000; Littlefield and Fowler, 2008; Ono, 2010; Sanger et al., 2005). allow Fhod32/2 embryos to develop further. Moreover, cardiomyopathic changes with immature myofibrils are caused in mice overexpressing a mutant Fhod3, defective in binding to actin. These findings indicate that actin dynamics, regulated by Fhod3, participate in sarcomere organization during myofibrillogenesis and thus play a crucial role in heart development. |
