Functional study of PAXBP1 in adult muscle satellite cells

Abstract

Vertebrate skeletal muscles possess remarkable regenerative capacity in response to injury due to the presence of muscle stem cells, also called muscle satellite cells (MuSC). Adult MuSC are quiescent under normal conditions, but become activated after injury. Activated satellite cells re-enter the cell cycle to generate a large pool of myogenic precursor cells (MPCs), and these MPCs will then differentiate and fuse to form new myofibers. PAX7 is a well-characterized marker for MuSC and is indispensable for injury-induced muscle regeneration. However, the exact role of PAX7 remains largely unknown. PAXBP1 is a novel PAX7-interacting protein identified by our group using yeast two hybrid screening. In cell culture models, both PAX7 and PAXBP1 are required for MuSC proliferation. However, different from PAX7, PAXBP1 also regulates myoblast differentiation in culture, suggesting PAXBP1 also plays PAX7 independent roles. To elucidate the roles of PAXBP1 in vivo in adult MuSC, our group generated inducible MuSC-specific Paxbp1 knockout (KO) mice. Preliminary data showed that PAXBP1 was not required for MuSC maintenance in uninjured muscles but indispensable for injury-induced muscle regeneration. Specifically, the quiescent PAXBP1-null MuSC failed to enter the cell cycle after injury, which resulted in a total block of injury-induced muscle regeneration. Indeed, RNA-seq data revealed a global downregulation of positive regulators of the cell cycle in KO cells. Moreover, the PAXBP1-null MuSC displayed severe morphology and motility defect. Our results demonstrated that PAXBP1 has crucial functions in adult MuSC in vivo. Next, we will try to rescue the defects of KO cells using potential PAXBP1 target genes. In addition, we will look for new PAXBP1 binding partners for better understandings of the underlying molecular mechanism by which PAXBP1 regulates the cell cycle re-entry from the quiescent MuSC after injury.

Date of Award	2017
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology