Regulation of MuSK Expression by a Novel Signaling Pathway

Chang-Hoon Kim,Wen C Xiong,Lin Mei

doi:10.1074/jbc.m305058200

Chang-Hoon Kim, Wen C Xiong + Show 1 more

Open Access

https://doi.org/10.1074/jbc.m305058200

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Abstract

MuSK is a receptor tyrosine kinase essential for neuromuscular junction formation. Expression of the MuSK gene is tightly regulated during development and at the neuromuscular junction. However, little is known about molecular mechanisms regulating its gene expression. Here we report a characterization of the promoter of the mouse MuSK gene. The transcription of MuSK starts at multiple sites with a major site 51 nt upstream of the translation start site. We have identified an E-box-like cis-element that is both required and sufficient for differentiation-dependent transcription. Interestingly, the promoter activity of the MuSK gene did not respond to neuregulin, a factor believed to mediate the synapse-specific transcription of acetylcholine receptor subunit genes. Rather, MuSK expression is increased in muscle cells stimulated with Wnt or at conditions when the Wnt signaling was activated. These results suggest a novel mechanism for the MuSK synapse-specific expression.

Highlights

MuSK is a receptor tyrosine kinase essential for neuromuscular junction formation
The promoter activity of the MuSK gene did not respond to neuregulin, a factor believed to mediate the synapsespecific transcription of acetylcholine receptor subunit genes
These results suggest a novel mechanism for the MuSK synapse-specific expression

Summary

Introduction

MuSK is a receptor tyrosine kinase essential for neuromuscular junction formation. Expression of the MuSK gene is tightly regulated during development and at the neuromuscular junction. Muscle-specific Activation and Regulation by Differentiation of the MuSK Promoter—To study the mechanisms regulating MuSK expression, we generated a reporter transgene containing the 4830-nt 5Ј-flanking region and the gene of firefly luciferase, M4830-Luc. The luciferase activity of the reporter, expressed as relative luciferase activity over cotransfected pRL-CMV, was similar to that of the empty vector pGL2-Basic in monkey kidney COS-7, HEK293 cells, or C2C12 myoblasts, suggesting that the promoter activity of MuSK was minimal in nonmuscle or undifferentiated muscle cells (Fig. 2A).

Results

Conclusion