THESIS
2019
viii, 129 pages : illustrations (some color) ; 30 cm
Abstract
Myogenic differentiation is a complex and highly orchestrated process that involves
many molecules and pathways. With intensive studies, both in vivo and in vitro, in the
past decades by many groups, we have gained a good knowledge about the molecular
mechanisms that regulate myogenic differentiation. However, gaps still exist. In our
current study, we aimed to identify key kinases that are involved in myogenic
differentiation. In an RNAi-based screening for protein kinases involved in C2C12
myoblast differentiation, we identified Stk24 (also called Mst3), a member of the
mammalian Ste20 family, as one of the key regulators required for myoblast
differentiation. When Stk24 was knocked down in cell culture models or in zebrafish,
the myogenic differentiation was suppressed. To e...[
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Myogenic differentiation is a complex and highly orchestrated process that involves
many molecules and pathways. With intensive studies, both in vivo and in vitro, in the
past decades by many groups, we have gained a good knowledge about the molecular
mechanisms that regulate myogenic differentiation. However, gaps still exist. In our
current study, we aimed to identify key kinases that are involved in myogenic
differentiation. In an RNAi-based screening for protein kinases involved in C2C12
myoblast differentiation, we identified Stk24 (also called Mst3), a member of the
mammalian Ste20 family, as one of the key regulators required for myoblast
differentiation. When Stk24 was knocked down in cell culture models or in zebrafish,
the myogenic differentiation was suppressed. To explore the role of Stk24 in vivo, we
generated a Stk24 knockout (KO) mouse strain by CRISPR/Cas9. The Stk24-null mice
had fewer quiescent muscle satellite cells (MuSC) than the wild-type control.
Consistently, the Stk24 KO mice displayed delayed muscle regeneration compared to
the wild-type mice. When we isolated and examined Stk24-null MuSC in culture, they
also showed defective myogenic differentiation with relatively normal proliferation.
Mechanistically, we found that key pro-differentiation factors like MyoD, MEF2A and
MEF2C were downregulated in Stk24-null myoblasts during differentiation. The
differentiation delay was partially mediated by the decreased activity of p38 MAPK, a
key MAPK required for myogenic differentiation. Furthermore, we also demonstrated
that Stk24 promotes the myogenic differentiation through the Limk2/Cofilin2 axis to
facilitate the formation of F-actin that is involved in cytoskeletal change during
myogenesis. Collectively, my research data reveal that Stk24 promotes myogenic
differentiation, both in cell culture and in vivo, through the p38 MAPK pathway and the
Limk2-Cofilin2 axis.
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