Characterization of follistatin-related gene as a negative regulatory factor for activin family members during mouse heart development.
Characterization of follistatin-related gene as a negative regulatory factor for activin family members during mouse heart development.
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DOI：
10.2152/jmi.54.276
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发表时间：
2007-08
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通讯作者：
Yuka Takehara-Kasamatsu;K. Tsuchida;M. Nakatani;T. Murakami;A. Kurisaki;O. Hashimoto;H. Ohuchi;Hitomi Kurose;Kazuhiro J. Mori;S. Kagami;S. Noji;H. Sugino
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文献类型：
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作者：
Yuka Takehara-Kasamatsu;K. Tsuchida;M. Nakatani;T. Murakami;A. Kurisaki;O. Hashimoto;H. Ohuchi;Hitomi Kurose;Kazuhiro J. Mori;S. Kagami;S. Noji;H. Sugino
卵泡抑素相关基因（FLRG）编码一种分泌糖蛋白，具有典型的富含半胱氨酸的卵泡抑素结构域。FLRG蛋白结合并中和几种转化生长因子- β (tgf - β)超家族成员，包括肌生长抑制素（MSTN），这是一种有效的骨骼肌质量负调节因子。我们之前报道过FLRG在胎儿和成年小鼠心脏中大量表达。本研究分析了FLRG mRNA在小鼠心脏发育过程中的表达。FLRG mRNA在胚胎心脏中持续表达，而在骨骼肌中表达极低。相比之下，MSTN mRNA在胚胎骨骼肌中高表达，而在心脏中低表达。原位杂交和免疫组化分析显示，FLRG在小鼠胚胎心脏主动脉和肺动脉平滑肌、二尖瓣和三尖瓣瓣小叶和心室心肌中表达。然而，MSTN在非常有限的区域表达，如肺动脉瓣和主动脉瓣小叶、室间隔顶部和房间隔。有趣的是，MSTN的表达与FLRG的表达是互补的，尤其是在瓣膜中。利用表面等离子体共振生物传感器和报告者实验进行的生化分析表明，FLRG一旦与MSTN和激活素结合，就很难与它们分离，并有效地抑制了这些活性。我们的研究结果表明，在心脏发育过程中，FLRG可能是激活包括MSTN在内的家族成员的负调节因子。
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-beta (TGF-beta) 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.