Key result
Wild-type Fhod3 rescues Fhod3-null cardiac defects and myofibrillogenesis, whereas an actin-binding mutant causes embryonic lethality.
Why the study?
The mechanisms by which Fhod3 regulates myofibrillogenesis during embryonic cardiogenesis remain largely unknown.
The actin-binding activity of the formin protein Fhod3 is essential for myofibril maturation and embryonic cardiogenesis.
No immediate clinical implications; leaves open Fhod3's role in human congenital cardiac defects.
Fhod3 is a cardiac member of the formin family proteins that play pivotal roles in actin filament assembly in various cellular contexts. The targeted deletion of mouse Fhod3 gene leads to defects in cardiogenesis, particularly during myofibrillogenesis, followed by lethality at embryonic day (E) 11.5. However, it remains largely unknown how Fhod3 functions during myofibrillogenesis. In this study, to assess the mechanism whereby Fhod3 regulates myofibrillogenesis during embryonic cardiogenesis, we generated transgenic mice expressing Fhod3 selectively in embryonic cardiomyocytes under the control of the β-myosin heavy chain (MHC) promoter. Mice expressing wild-type Fhod3 in embryonic cardiomyocytes survive to adulthood and are fertile, whereas those expressing Fhod3 (I1127A) defective in binding to actin die by E11.5 with cardiac defects. This cardiac phenotype of the Fhod3 mutant embryos is almost identical to that observed in Fhod3 null embryos, suggesting that the actin-binding activity of Fhod3 is crucial for embryonic cardiogenesis. On the other hand, the β-MHC promoter-driven expression of wild-type Fhod3 sufficiently rescues cardiac defects of Fhod3-null embryos, indicating that the Fhod3 protein expressed in a transgenic manner can function properly to achieve myofibril maturation in embryonic cardiomyocytes. Using the transgenic mice, we further examined detailed localization of Fhod3 during myofibrillogenesis in situ and found that Fhod3 localizes to the specific central region of nascent sarcomeres prior to massive rearrangement of actin filaments and remains there throughout myofibrillogenesis. Taken together, the present findings suggest that, during embryonic cardiogenesis, Fhod3 functions as the essential reorganizer of actin filaments at the central region of maturating sarcomeres via the actin-binding activity of the FH2 domain.
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Fujimoto et al. (2016) studied Embryonic cardiogenesis and myofibrillogenesis. Transgenic expression of Fhod3 (wild-type or I1127A mutant) vs. Nontransgenic wild-type or Fhod3-null embryos was evaluated on Embryonic survival and myofibril maturation. Transgenic expression of an actin-binding defective Fhod3 mutant causes embryonic lethality by E11.5, whereas wild-type Fhod3 rescues Fhod3-null cardiac defects, demonstrating its crucial role in myofibrillogenesis.
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