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A non-signaling role of Robo2 in tendons is essential for Slit processing and muscle patterning.

Development. 2015 Oct 15;142(20):3512-8. Epub 2015 Sep 23
Elly Ordan 1 , Talila Volk 2
Elly Ordan 1 , Talila Volk 2

[No authors listed]

Author information
  • 1 Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
  • 2 Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel talila.volk@weizmann.ac.il.

摘要


Coordinated locomotion of an organism relies on the development of proper musculoskeletal connections. In Drosophila, the Slit-Robo signaling pathway guides muscles to tendons. Here, we show that the Slit receptor Roundabout 2 (Robo2) plays a non-cell-autonomous role in directing muscles to their corresponding tendons. Robo2 is expressed by tendons, and its non-signaling activity in these cells promotes Slit cleavage, producing a cleaved Slit N-terminal guidance signal that provides short-range signaling into muscles. Consistently, robo2 mutant embryos exhibited a muscle phenotype similar to that of slit, which could not be rescued by muscle-specific Robo2 expression but rather by ectodermally derived Robo2. Alternatively, this muscle phenotype could be induced by tendon-specific robo2 We further show that membrane immobilization of Slit or its N-terminal cleaved form (Slit-N) on tendons bypasses the functional requirement for Robo2 in tendons, verifying that the major role of Robo2 is to promote the association of Slit with the tendon cell membrane. Slit-N tends to oligomerize whereas full-length uncleavable Slit does not. It is therefore proposed that Slit-N oligomers, produced at the tendon membrane by Robo2, signal to the approaching muscle by combined Robo1 and Robo3 activity. These findings establish a Robo2-mediated mechanism, independent of signaling, that is essential to limiting Slit distribution and which might be relevant to the regulation of Slit-mediated short-range signaling in additional systems.

KEYWORDS: Drosophila embryo, Muscle, Robo, Slit, Slit cleavage