Abstract
In recent years a number of the genes that regulate muscle formation and maintenance in higher organisms have been identified. Studies employing invertebrate and vertebrate model organisms have revealed that many of the genes required for early mesoderm specification are highly conserved throughout evolution. Less is known about the molecules that mediate the steps subsequent to myogenesis, e. g. myotube guidance and attachment to tendon cells. We use the stereotypic pattern of the Drosophila embryonic body wall musculature in genetic approaches to identify novel factors required for muscle attachment site selection. Here, we show that Wnt5 is needed in this process. The lateral transverse muscles frequently overshoot their target attachment sites and stably attach at novel epidermal sites in Wnt5 mutant embryos. Restoration of WNT5 expression in either the muscle or the tendon cell rescues the mutant phenotype. Surprisingly, the novel attachment sites in Wnt5 mutants frequently do not express the Stripe (SR) protein which has been shown to be required for terminal tendon cell differentiation. A muscle bypass phenotype was previously reported for embryos lacking the WNT5 receptor Derailed (DRL). drl and Wnt5 mutant embryos also exhibit axon path finding errors. DRL belongs to the conserved Ryk receptor tyrosine kinase family which includes two other Drosophila orthologs, the Doughnut on 2 (DNT) and Derailed-2 (DRL-2) proteins. We generated a mutant allele of dnt and find that dnt, but not Drl-2, mutant embryos also show a muscle bypass phenotype. Genetic interaction experiments indicate that drl and dnt act together, likely as WNT5 receptors, to control muscle attachment site selection. These results extend previous findings that at least some of the molecular pathways that guide axons towards their targets are also employed for guidance of muscle fibers to their appropriate attachment sites.
Highlights
The establishment of the musculature in higher organisms is a multistep process involving myoblast specification and fusion, followed by guidance of the myotubes towards the muscle attachment sites (MAS)
We find that WNT5, a secreted protein, expressed in either the tendon cells or the muscle fiber is sufficient to restore correct muscle attachment in Wnt5 mutant embryos
We find that 36%, 8%, 0% of hemisegments display a LTM muscle bypass phenotype when drl, dnt or Drl-2 is absent, respectively
Summary
The establishment of the musculature in higher organisms is a multistep process involving myoblast specification and fusion, followed by guidance of the myotubes towards the muscle attachment sites (MAS) (reviewed in [1]). Final differentiation of both the muscle and the attachment sites is initiated when the multinucleated fiber attaches to the tendon cell. Each embryonic somatic muscle fiber is formed by the fusion of a muscle founder cell and a number of fusion-competent myoblasts [9]. The fusion process creates multinucleated myofibers whose two leading edges subsequently migrate towards clusters of tendon cell progenitors in the epidermis [1,2,7]
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