The actin-organizing formin protein Fhod3 is required for postnatal development and functional maintenance of the adult heart in mice.

Tomoki Ushijima, Noriko Fujimoto, Sho Matsuyama, Meikun Kan-O, Hiroshi Kiyonari, Go Shioi, Yohko Kage, Sho Yamasaki, Ryu Takeya, Hideki Sumimoto

The Journal of biological chemistry 2018 Jan 05

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Cardiac development and function require actin-myosin interactions in the sarcomere, a highly organized contractile structure. Sarcomere assembly mediated by formin homology 2 domain-containing 3 (Fhod3), a member of formins that directs formation of straight actin filaments, is essential for embryonic cardiogenesis. However, the role of Fhod3 in the neonatal and adult stages has remained unknown. Here, we generated floxed Fhod3 mice to bypass the embryonic lethality of an Fhod3 knockout (KO). Perinatal KO of Fhod3 in the heart caused juvenile lethality at around day 10 after birth with enlarged hearts composed of severely impaired myofibrils, indicating that Fhod3 is crucial for postnatal heart development. Tamoxifen-induced conditional KO of Fhod3 in the adult heart neither led to lethal effects nor did it affect sarcomere structure and localization of sarcomere components. However, adult Fhod3-deleted mice exhibited a slight cardiomegaly and mild impairment of cardiac function, conditions that were sustained over 1 year without compensation during aging. In addition to these age-related changes, systemic stimulation with the α1-adrenergic receptor agonist phenylephrine, which induces sustained hypertension and hypertrophy development, induced expression of fetal cardiac genes that was more pronounced in adult Fhod3-deleted mice than in the control mice, suggesting that Fhod3 modulates hypertrophic changes in the adult heart. We conclude that Fhod3 plays a crucial role in both postnatal cardiac development and functional maintenance of the adult heart. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Citation

Tomoki Ushijima, Noriko Fujimoto, Sho Matsuyama, Meikun Kan-O, Hiroshi Kiyonari, Go Shioi, Yohko Kage, Sho Yamasaki, Ryu Takeya, Hideki Sumimoto. The actin-organizing formin protein Fhod3 is required for postnatal development and functional maintenance of the adult heart in mice. The Journal of biological chemistry. 2018 Jan 05;293(1):148-162