Robo2 acts in trans to inhibit Slit-Robo1 repulsion in pre-crossing commissural axons

Evans, Tony; Santiago, Celine; Arbeille, Elise; Bashaw, Greg J.

doi:10.7554/elife.08407

Cited by 76 publications

(121 citation statements)

References 47 publications

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“…4M). In this context the Robo2 cytoplasmic signaling domain is dispensable, consistent with Robo2 function in chordotonal organs (Kraut and Zinn, 2004) and with Robo2 non-autonomous function in the CNS (Evans et al, 2015).…”

Section: Robo2 Enhances Slit Cleavagementioning

confidence: 76%

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

Ordan

Volk

2015

Development

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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 RNAi. We further show that membrane immobilization of Slit or its Nterminal 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 shortrange signaling in additional systems.

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Section: Robo2 Enhances Slit Cleavagementioning

confidence: 76%

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

Ordan

Volk

2015

Development

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“…In addition, no vertebrate homolog of Comm has been identified to date, suggesting that other mechanisms must regulate Slit-Robo repulsion in commissural axons in higher organisms. In Drosophila, another mechanism also regulates chemorepulsive signaling in pre-crossing axons: Robo2 expressed in midline cells at the time of crossing binds in trans to Robo1 on commissural axons, thereby inhibiting Slit-mediated repulsion (Evans et al, 2015). Interesting in this context is the finding that Robo1 and Robo2 show homophilic binding properties in mammalian systems and interaction in trans can promote axon outgrowth of retinal neurons (Hivert et al, 2002).…”

Section: The Spatiotemporal Gating Of Slit Responsiveness In Roboexprmentioning

confidence: 99%

Slit-Robo signaling

2016

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Slits are secreted proteins that bind to Roundabout (Robo) receptors. Slit-Robo signaling is best known for mediating axon repulsion in the developing nervous system. However, in recent years the functional repertoire of Slits and Robo has expanded tremendously and Slit-Robo signaling has been linked to roles in neurogenesis, angiogenesis and cancer progression among other processes. Likewise, our mechanistic understanding of Slit-Robo signaling has progressed enormously. Here, we summarize new insights into Slit-Robo evolutionary and system-dependent diversity, receptor-ligand interactions, signaling crosstalk and receptor activation.

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“…Although in determining the distance from the midline all 3 Robos are interchangeable, for other roles, e.g., neuronal crossing of the midline, they maintain distinct functions. 2,3,15 Slit, Robo, and Robo2 are important players in the process of muscle elongation but the exact nature of their contribution has not been directly addressed. 7 Slit is expressed by the tendon cells while Robo is expressed in the elongating muscle.…”

mentioning

confidence: 99%