Editors' ChoiceDevelopmental Biology

Slit halts muscles

Sci. Signal.  14 Apr 2015:
Vol. 8, Issue 372, pp. ec94
DOI: 10.1126/scisignal.aab3227

During development, muscles elongate towards and attach to tendons. Tendons produce the secreted guidance cue Slit, which has been reported to both repel and attract muscles, depending upon the context. Slit is cleaved into a large N-terminal fragment (Slit-N), which contains the binding site for the repulsive receptor Robo, and a small C-terminal fragment (Slit-C), but whether both fragments have biological activity is unclear. Ordan et al. found that Slit-N mediated repulsion and arrested migration of muscles in Drosophila melanogaster embryos. Embryos lacking Slit had abnormally oriented muscles consistent with an absence of repulsive cues. Although an uncleavable form of Slit (Slit-UC) did not rescue these phenotypes, a membrane-anchored form of Slit-UC did, suggesting that cleavage-dependent immobilization of Slit on the tendon cell membrane was important for proper Slit function. Microscopy and Western blotting analysis of knock-in flies carrying alleles that encoded various forms of epitope-tagged Slit (wild-type full-length, membrane-anchored full-length, uncleavable, membrane-anchored uncleavable or membrane-anchored Slit-N) indicated that only membrane-associated forms of uncleavable full-length Slit and Slit-N accumulated on tendon cell membranes and that membrane association protected Slit from degradation. When fluorescently tagged proteins were overexpressed in tendon cells, Slit-UC diffused away from muscle attachment sites, but Slit-N remained on the tendon cells. Slit-N repelled migrating muscles away from segmental borders in vivo, consistent with the known repulsive role of Slit in neuronal migration. Thus, cleavage of Slit produces an N-terminal fragment that, through an unknown mechanism, associates with tendon cell membranes and halts muscle migration so that the muscles can attach to the tendons. In this context, the C-terminal fragment is likely degraded.

E. Ordan, M. Brankatschk, B. Dickson, F. Schnorrer, T. Volk, Slit cleavage is essential for producing an active, stable, non-diffusible short-range signal that guides muscle migration. Development 142, 1431–1436 (2015). [PubMed]

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