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Published online 18 April 2005. doi:10.1083/jcb.200501156
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 169, Number 2, 257-268
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Article

 Transcriptional regulation of myotube fate specification and intrafusal muscle fiber morphogenesis

Y'vonne Albert1, Jennifer Whitehead1, Laurie Eldredge1, John Carter1, Xiaoguang Gao1, and Warren G. Tourtellotte1,2,3

1 Department of Pathology, Northwestern University, Chicago, IL 60611
2 Neurology, Northwestern University, Chicago, IL 60611
3 The Institute for Neuroscience, Northwestern University, Chicago, IL 60611

Correspondence to Warren G. Tourtellotte: warren{at}northwestern.edu

Vertebrate muscle spindle stretch receptors are important for limb position sensation (proprioception) and stretch reflexes. The structurally complex stretch receptor arises from a single myotube, which is transformed into multiple intrafusal muscle fibers by sensory axon–dependent signal transduction that alters gene expression in the contacted myotubes. The sensory-derived signal transduction pathways that specify the fate of myotubes are very poorly understood. The zinc finger transcription factor, early growth response gene 3 (Egr3), is selectively expressed in sensory axon–contacted myotubes, and it is required for normal intrafusal muscle fiber differentiation and spindle development. Here, we show that overexpression of Egr3 in primary myotubes in vitro leads to the expression of a particular repertoire of genes, some of which we demonstrate are also regulated by Egr3 in developing intrafusal muscle fibers within spindles. Thus, our results identify a network of genes that are regulated by Egr3 and are involved in intrafusal muscle fiber differentiation. Moreover, we show that Egr3 mediates myotube fate specification that is induced by sensory innervation because skeletal myotubes that express Egr3 independent of other sensory axon regulation are transformed into muscle fibers with structural and molecular similarities to intrafusal muscle fibers. Hence, Egr3 is a target gene that is regulated by sensory innervation and that mediates gene expression involved in myotube fate specification and intrafusal muscle fiber morphogenesis.

Abbreviations used in this paper: Arc, activity-regulated cytoskeletal-associated protein; DRG, dorsal root ganglion; E, embryonic gestational day; Egr3, early growth response gene 3; ErbB2, erythroblastic leukemia viral oncogene homologue 2; ERE, early growth response element; ERM, Ets-related protein; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GDNF, glial-derived neurotrophic factor; GPR50, g-coupled protein receptor 50; Hey1, harry enhance of split 1; HSA, human skeletal actin; MOI, multiplicity of infection; NGFR (p75), low affinity nerve growth factor receptor; Nrg1, neuregulin-1; NT-3, neurotrophin-3; Prph1, peripherin 1; Pv, parvalbumin; Rhpn2, rhophilin 2; Sd-MyHC, slow developmental myosin heavy chain; SSTr2, somatostatin receptor type 2.


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