Characterization of follistatin-related gene as a negative regulatory factor for activin family members during mouse heart development

Yuka Takehara-Kasamatsu, Kunihiro Tsuchida, Masashi Nakatani, Tatsuya Murakami, Akira Kurisaki, Osamu Hashimoto, Hideyo Ohuchi, Hitomi Kurose, Kazuhiro Mori, Shoji Kagami, Sumihare Noji, Hiromu Sugino

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)


Follistatin-related gene (FLRG) encodes a secretory glycoprotein that has characteristic cysteine-rich follistatin domains. FLRG protein binds to and neutralizes several transforming growth factor-β (TGF-β) superfamily members, including myostatin (MSTN), which is a potent negative regulator of skeletal muscle mass. We have previously reported that FLRG was abundantly expressed in fetal and adult mouse heart. In this study, we analyzed the expression of FLRG mRNA during mouse heart development. FLRG mRNA was continuously expressed in the embryonic heart, whereas it was very low in skeletal muscles. By contrast, MSTN mRNA was highly expressed in embryonic skeletal muscles, whereas the expression of MSTN mRNA was rather low in the heart. In situ hybridization and immunohistochemical analysis revealed that FLRG expressed in smooth muscle of the aorta and pulmonary artery, valve leaflets of mitral and tricuspid valves, and cardiac muscles in the ventricle of mouse embryonic heart. However, MSTN was expressed in very limited areas, such as valve leaflets of pulmonary and aortic valves, the top of the ventricular and atrial septa. Interestingly, the expression of MSTN was complementary to that of FLRG, especially in the valvular apparatus. Biochemical analyses with surface plasmon resonance biosensor and reporter assays demonstrated that FLRG hardly dissociates from MSTN and activin once it bound to them, and efficiently inhibits these activities. Our results suggest that FLRG could function as a negative regulator of activin family members including MSTN during heart development.

Original languageEnglish
Pages (from-to)276-288
Number of pages13
JournalJournal of Medical Investigation
Issue number3-4
Publication statusPublished - 2007
Externally publishedYes


  • Activin
  • FLRG
  • Follistatin
  • Heart
  • Myostatin

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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