Intracellular Trafficking Mechanisms that Regulate Repulsive Axon Guidance

Sullivan, Kelly G.; Bashaw, Greg J.

doi:10.1016/j.neuroscience.2022.07.012

Cited by 3 publications

(3 citation statements)

References 88 publications

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“…Our finding that high-level over-expression of the Comm2PY mutant variant that cannot inhibit Robo1 surface expression can still inhibit midline repulsion is consistent with mechanism of regulation that is independent of protein degradation of Robo1, or another Comm substrate. One interesting potential alternative role for Comm would be to prevent Robo1 endocytosis, since receptor endocytosis is required for repulsive signaling (Chance and Bashaw, 2015; Sullivan and Bashaw, 2023). Indeed, at the Drosophila neuromuscular junction (NMJ), Comm has been proposed to regulate endocytosis from the plasma membrane to promote synapse formation (Ing et al, 2007; Wolf et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

“…One interesting potential alternative role for Comm would be to prevent Robo1 endocytosis, since receptor endocytosis is required for repulsive signaling (Chance and Bashaw, 2015;Sullivan and Bashaw, 2023). Indeed, at the Drosophila neuromuscular junction (NMJ), Comm has been proposed to regulate endocytosis from the plasma membrane to promote synapse formation (Ing et al, 2007;Wolf et al, 1998).…”

Section: Comm Is Likely To Regulate Robo1 Repulsion Through Multiple ...mentioning

confidence: 99%

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Commissureless acts as a substrate adapter in a conserved Nedd4 E3 ubiquitin ligase pathway to promote axon growth across the midline

Sullivan,

Bashaw

2023

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In both vertebrates and invertebrates, commissural neurons prevent premature responsiveness to the midline repellant Slit by downregulating surface levels of its receptor Roundabout1 (Robo1). InDrosophila, Commissureless (Comm) plays a critical role in this process; however, there is conflicting data on the underlying molecular mechanism. Here, we demonstrate that the conserved PY motifs in the cytoplasmic domain of Comm are required allow the ubiquitination and lysosomal degradation of Robo1. Disruption of these motifs prevents Comm from localizing to Lamp1 positive late endosomes and to promote axon growth across the midlinein vivo. In addition, we conclusively demonstrate a role for Nedd4 in midline crossing. Genetic analysis shows thatnedd4mutations result in midline crossing defects in the Drosophila embryonic nerve cord, which can be rescued by introduction of exogenous Nedd4. Biochemical evidence shows that Nedd4 incorporates into a three-member complex with Comm and Robo in a PY motif-dependent manner. Finally, we present genetic evidence that Nedd4 acts with Comm in the embryonic nerve cord to downregulate Robo1 levels. Taken together, these findings demonstrate that Comm promotes midline crossing in the nerve cord by facilitating Robo ubiquitination by Nedd4, ultimately leading to its degradation.

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Section: Discussionmentioning

confidence: 99%

Section: Comm Is Likely To Regulate Robo1 Repulsion Through Multiple ...mentioning

confidence: 99%

Commissureless acts as a substrate adapter in a conserved Nedd4 E3 ubiquitin ligase pathway to promote axon growth across the midline

Sullivan,

Bashaw

2023

Preprint

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show abstract

“…Our finding that high-level overexpression of the Comm2PY mutant variant that cannot inhibit Robo1 surface expression can still inhibit midline repulsion is consistent with mechanism of regulation that is independent of protein degradation of Robo1, or another Comm substrate. One interesting potential alternative role for Comm would be to prevent Robo1 endocytosis, since receptor endocytosis is required for repulsive signaling (Chance and Bashaw, 2015 ;Sullivan and Bashaw, 2023 ). Indeed, at the Drosophila neuromuscular junction (NMJ), Comm has been proposed to regulate endocytosis from the plasma membrane to promote synapse formation (Ing et al, 2007 ;Wolf et al, 1998 ).…”

Section: Comm Is Likely To Regulate Robo1 Repulsion Through Multiple ...mentioning

confidence: 99%

Commissureless acts as a substrate adapter in a conserved Nedd4 E3 ubiquitin ligase pathway to promote axon growth across the midline

Sullivan,

Bashaw

2024

Preprint

Self Cite

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In both vertebrates and invertebrates, commissural neurons prevent premature responsiveness to the midline repellant Slit by downregulating surface levels of its receptor Roundabout1 (Robo1). In Drosophila , Commissureless (Comm) plays a critical role in this process; however, there is conflicting data on the underlying molecular mechanism. Here, we demonstrate that the conserved PY motifs in the cytoplasmic domain of Comm are required allow the ubiquitination and lysosomal degradation of Robo1. Disruption of these motifs prevents Comm from localizing to Lamp1 positive late endosomes and to promote axon growth across the midline in vivo . In addition, we conclusively demonstrate a role for Nedd4 in midline crossing. Genetic analysis shows that nedd4 mutations result in midline crossing defects in the Drosophila embryonic nerve cord, which can be rescued by introduction of exogenous Nedd4. Biochemical evidence shows that Nedd4 incorporates into a three-member complex with Comm and Robo in a PY motif-dependent manner. Finally, we present genetic evidence that Nedd4 acts with Comm in the embryonic nerve cord to downregulate Robo1 levels. Taken together, these findings demonstrate that Comm promotes midline crossing in the nerve cord by facilitating Robo ubiquitination by Nedd4, ultimately leading to its degradation.

show abstract

Commissureless acts as a substrate adapter in a conserved Nedd4 E3 ubiquitin ligase pathway to promote axon growth across the midline

Sullivan,

Bashaw

2024

Preprint

Self Cite

View full text Add to dashboard Cite

In both vertebrates and invertebrates, commissural neurons prevent premature responsiveness to the midline repellant Slit by downregulating surface levels of its receptor Roundabout1 (Robo1). In Drosophila , Commissureless (Comm) plays a critical role in this process; however, there is conflicting data on the underlying molecular mechanism. Here, we demonstrate that the conserved PY motifs in the cytoplasmic domain of Comm are required allow the ubiquitination and lysosomal degradation of Robo1. Disruption of these motifs prevents Comm from localizing to Lamp1 positive late endosomes and to promote axon growth across the midline in vivo . In addition, we conclusively demonstrate a role for Nedd4 in midline crossing. Genetic analysis shows that nedd4 mutations result in midline crossing defects in the Drosophila embryonic nerve cord, which can be rescued by introduction of exogenous Nedd4. Biochemical evidence shows that Nedd4 incorporates into a three-member complex with Comm and Robo in a PY motif-dependent manner. Finally, we present genetic evidence that Nedd4 acts with Comm in the embryonic nerve cord to downregulate Robo1 levels. Taken together, these findings demonstrate that Comm promotes midline crossing in the nerve cord by facilitating Robo ubiquitination by Nedd4, ultimately leading to its degradation.

show abstract

Intracellular Trafficking Mechanisms that Regulate Repulsive Axon Guidance

Cited by 3 publications

References 88 publications

Commissureless acts as a substrate adapter in a conserved Nedd4 E3 ubiquitin ligase pathway to promote axon growth across the midline

Commissureless acts as a substrate adapter in a conserved Nedd4 E3 ubiquitin ligase pathway to promote axon growth across the midline

Commissureless acts as a substrate adapter in a conserved Nedd4 E3 ubiquitin ligase pathway to promote axon growth across the midline

Commissureless acts as a substrate adapter in a conserved Nedd4 E3 ubiquitin ligase pathway to promote axon growth across the midline

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