Hesr1 and Hesr3 are essential to generate undifferentiated quiescent satellite cells and to maintain satellite cell numbers

作者：So‐ichiro Fukada, Masahiko Yamaguchi, Hiroki Kokubo, Ryo Ogawa, Akiyoshi Uezumi, Tomohiro Yoneda, Miroslav M. Matev, Norio Motohashi, Takahito Ito, Anna Żółkiewska, Randy L. Johnson, Yumiko Saga, Yuko Miyagoe‐Suzuki, Kazutake Tsujikawa, Shin’ichi Takeda, Hiroshi Yamamoto · 发表于：Development · 年份：2011 · DOI：10.1242/dev.067165 · 被引用次数：165 · 研究领域：Muscle Physiology and Disorders、Tissue Engineering and Regenerative Medicine、Spaceflight effects on biology

Satellite cells, which are skeletal muscle stem cells, divide to provide new myonuclei to growing muscle fibers during postnatal development, and then are maintained in an undifferentiated quiescent state in adult skeletal muscle. This state is considered to be essential for the maintenance of satellite cells, but their molecular regulation is unknown. We show that Hesr1 (Hey1) and Hesr3 (Heyl) (which are known Notch target genes) are expressed simultaneously in skeletal muscle only in satellite cells. In Hesr1 and Hesr3 single-knockout mice, no obvious abnormalities of satellite cells or muscle regenerative potentials are observed. However, the generation of undifferentiated quiescent satellite cells is impaired during postnatal development in Hesr1/3 double-knockout mice. As a result, myogenic (MyoD and myogenin) and proliferative (Ki67) proteins are expressed in adult satellite cells. Consistent with the in vivo results, Hesr1/3-null myoblasts generate very few Pax7(+) MyoD(-) undifferentiated cells in vitro. Furthermore, the satellite cell number gradually decreases in Hesr1/3 double-knockout mice even after it has stabilized in control mice, and an age-dependent regeneration defect is observed. In vivo results suggest that premature differentiation, but not cell death, is the reason for the reduced number of satellite cells in Hesr1/3 double-knockout mice. These results indicate that Hesr1 and Hesr3 are essential for the generation of adult satellite cells and for the ma...