Abstract
Navigation of motoneuronal growth cones toward the somatic musculature in Drosophila serves as a model system to unravel the molecular mechanisms of axon guidance and target selection. In a large-scale mutagenesis screen, we identified piranha, a motor axon guidance mutant that shows strong defects in the neuromuscular connectivity pattern. In piranha mutant embryos, permanent defasciculation errors occur at specific choice points in all motor pathways. Positional cloning of piranha revealed point mutations in tolloid-related 1 (tlr1), an evolutionarily conserved gene encoding a secreted metalloprotease. Ectopic expression of Tlr1 in several tissues of piranha mutants, including hemocytes, completely restores the wild-type innervation pattern, indicating that Tlr1 functions cell non-autonomously. We further show that loss-of-function mutants of related metalloproteases do not have motor axon guidance defects and that the respective proteins cannot functionally replace Tlr1. tlr1, however, interacts with sidestep, a muscle-derived attractant. Double mutant larvae of tlr1 and sidestep show an additive phenotype and lack almost all neuromuscular junctions on ventral muscles, suggesting that Tlr1 functions together with Sidestep in the defasciculation process.
Highlights
Accurate innervation of somatic muscles is a prerequisite for coordinated movements in any higher organism
Piranha mutant larvae display a high degree of missing and mislocalized neuromuscular junctions (NMJs) In Drosophila embryos and larvae, the somatic musculature of abdominal segments A2-A7 consists of 30 muscles that are individually identifiable and innervated at invariant positions (Fig. 1A)
It binds to the postsynaptic protein Discs large (Dlg) and highlights all NMJs consisting of type Ib and Is boutons (Zito et al, 1999)
Summary
Accurate innervation of somatic muscles is a prerequisite for coordinated movements in any higher organism. Correct neuromuscular connectivity is established by the developmental processes of axon outgrowth, axon guidance, target selection and synapse formation (Tessier-Lavigne and Goodman, 1996). Despite the fact that motor axons initially form coherent nerve bundles, certain growth cones leave these tightly fasciculated nerves at specific peripheral locations in order to migrate into their target regions. Defasciculation, the exit of axons from a nerve track, is a crucial process that needs to be strictly regulated. Failure to defasciculate at these choice points leads to axon guidance defects and muscle innervation errors (Araujo and Tear, 2003). Which molecules regulate the detachment of motor axons from adherent nerve bundles? Which molecules regulate the detachment of motor axons from adherent nerve bundles? How are choice points molecularly defined?
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