Cry2 Is Critical for Circadian Regulation of Myogenic Differentiation by Bclaf1-Mediated mRNA Stabilization of Cyclin D1 and Tmem176b
Matthew Lowe,
Jacob Lage,
Ellen Paatela,
Dane Munson,
Reilly Hostager,
Ce Yuan,
Nobuko Katoku-Kikyo,
Mercedes Ruiz-Estevez,
Yoko Asakura,
James Staats,
Mulan Qahar,
Michaela Lohman,
Atsushi Asakura,
Nobuaki Kikyo
Affiliations
Matthew Lowe
Stem Cell Institute , University of Minnesota, Minneapolis, MN 55455, USA; Department of Genetics, Cell Biology, and Development , University of Minnesota, Minneapolis, MN 55455, USA
Jacob Lage
Stem Cell Institute , University of Minnesota, Minneapolis, MN 55455, USA; Department of Genetics, Cell Biology, and Development , University of Minnesota, Minneapolis, MN 55455, USA
Ellen Paatela
Stem Cell Institute , University of Minnesota, Minneapolis, MN 55455, USA
Dane Munson
Stem Cell Institute , University of Minnesota, Minneapolis, MN 55455, USA
Reilly Hostager
Stem Cell Institute , University of Minnesota, Minneapolis, MN 55455, USA
Ce Yuan
Stem Cell Institute , University of Minnesota, Minneapolis, MN 55455, USA; Bioinformatics and Computational Biology Graduate Program , University of Minnesota, Minneapolis, MN 55455, USA
Nobuko Katoku-Kikyo
Stem Cell Institute , University of Minnesota, Minneapolis, MN 55455, USA; Department of Neurology , University of Minnesota, Minneapolis, MN 55455, USA
Mercedes Ruiz-Estevez
Stem Cell Institute , University of Minnesota, Minneapolis, MN 55455, USA; Department of Genetics, Cell Biology, and Development , University of Minnesota, Minneapolis, MN 55455, USA
Yoko Asakura
Stem Cell Institute , University of Minnesota, Minneapolis, MN 55455, USA; Department of Genetics, Cell Biology, and Development , University of Minnesota, Minneapolis, MN 55455, USA
James Staats
Stem Cell Institute , University of Minnesota, Minneapolis, MN 55455, USA; Department of Genetics, Cell Biology, and Development , University of Minnesota, Minneapolis, MN 55455, USA
Mulan Qahar
Stem Cell Institute , University of Minnesota, Minneapolis, MN 55455, USA; Department of Neurology , University of Minnesota, Minneapolis, MN 55455, USA
Michaela Lohman
Stem Cell Institute , University of Minnesota, Minneapolis, MN 55455, USA
Atsushi Asakura
Stem Cell Institute , University of Minnesota, Minneapolis, MN 55455, USA; Department of Neurology , University of Minnesota, Minneapolis, MN 55455, USA; Corresponding author
Nobuaki Kikyo
Stem Cell Institute , University of Minnesota, Minneapolis, MN 55455, USA; Department of Genetics, Cell Biology, and Development , University of Minnesota, Minneapolis, MN 55455, USA; Corresponding author
Summary: Circadian rhythms regulate cell proliferation and differentiation; however, little is known about their roles in myogenic differentiation. Our synchronized differentiation studies demonstrate that myoblast proliferation and subsequent myotube formation by cell fusion occur in circadian manners. We found that one of the core regulators of circadian rhythms, Cry2, but not Cry1, is critical for the circadian patterns of these two critical steps in myogenic differentiation. This is achieved through the specific interaction between Cry2 and Bclaf1, which stabilizes mRNAs encoding cyclin D1, a G1/S phase transition regulator, and Tmem176b, a transmembrane regulator for myogenic cell fusion. Myoblasts lacking Cry2 display premature cell cycle exit and form short myotubes because of inefficient cell fusion. Consistently, muscle regeneration is impaired in Cry2−/− mice. Bclaf1 knockdown recapitulated the phenotypes of Cry2 knockdown: early cell cycle exit and inefficient cell fusion. This study uncovers a post-transcriptional regulation of myogenic differentiation by circadian rhythms.
