Role of the actin-organizing formin Fhod3 in cardiac hypertrophy and the pathogenesis of cardiomyopathy

[Speaker] Ryu Takeya:1
[Co-author] Sho Matsuyama:1, Yohko Kage:1, Noriko Fujimoto:2, Tomoki Ushijima:2, Hideki Sumimoto:2
1:Department of Pharmacology, Faculty of Medicine, University of Miyazaki, Japan, 2:Department of Biochemistry, Kyushu University Graduate School of Medical Sciences, Japan

Development and functional maintenance of the heart require actin-myosin interactions in the sarcomere, a highly organized contractile structure. Sarcomere assembly during embryonic cardiogenesis is mediated by formin homology 2 domain-containing 3 (Fhod3), a member of formins that direct formation of straight actin filaments. However, the role of Fhod3 after birth has remained unknown. We generated Fhod3 conditional knockout (KO) mice using the Cre/loxP system to bypass the embryonic lethality. Perinatal KO of Fhod3 in the heart resulted in juvenile lethality with severely impaired myofibrils, indicating that Fhod3 is crucial for postnatal heart development. In contrast, tamoxifen-induced conditional KO of Fhod3 in the adult heart was neither led to lethal nor affected sarcomere structure. However, adult Fhod3-deleted mice exhibited a slight cardiomegaly and mild impairment of cardiac function, indicating that Fhod3 also plays a role in functional maintenance of the adult heart. In order to clarify the mechanism of action of Fhod3, we have identified Fhod3-associating proteins using immunoprecipitation/mass spectrometric analysis. The direct interaction of Fhod3 with a sarcomeric protein identified may serve to control the Fhod3-mediated actin turnover in the cardiac sarcomere. We will discuss the role of actin dynamics in cardiac sarcomeres with implications for cardiac function.
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