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Updated: May 16, 2026
Retrograde Tracing of Drosophila Embryonic Motor Neurons Using Lipophilic Fluorescent Dyes
Published on: January 12, 2020
Drosophila Vap-33 is required for axonal localization of Dscam isoforms
Zhen Yang1, Sung Un Huh, J Michelle Drennan
1Department of Biochemistry, Purdue University, West Lafayette, Indiana 47907, USA.
Abstract:
Mutations in VAPB have been identified in a familial form of amyotrophic lateral sclerosis (ALS), and reduced VAPB levels have been found in patients with sporadic ALS. Vap protein family members from different species and cell types have been implicated in a number of cellular functions, but how Vap dysfunction in neurons and/or muscles contributes to motor neuron degeneration and death is poorly understood. Using Drosophila as a model organism, we show that Vap physically interacts with and affects the axonal functions of the Down syndrome cell adhesion molecule (Dscam). Dscam is a cell-surface receptor involved in axon and dendritic patterning and neuron self-recognition and avoidance. Alternative splicing of the Dscam transcript leads to the production of Dscam isoforms that contain one of two possible transmembrane (TM) domain and flanking sequences that either restrict the isoform to dendrites and cell bodies (TM1) or target the isoform to axon processes (TM2). We find that Vap specifically interacts with Dscam isoforms that contain the TM2 cytoplasmic juxtamembrane flanking sequences. Using loss-of-function genetics, we further show that Vap is required for localization of Dscam isoforms containing TM2 to axons and that Vap loss suppresses Dscam gain-of-function axon phenotypes. We propose that Vap function is required in neurons to selectively traffic proteins to axons, and disruption of this function may contribute to the pathology of ALS.
Insights
Vesicle-associated membrane protein-associated protein B (VAPB) is crucial for motor neuron health. This study reveals VAPB’s role in trafficking Down syndrome cell adhesion molecule (Dscam) to axons, suggesting its dysfunction contributes to amyotrophic lateral sclerosis (ALS) pathology.
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Mutations in VAPB are linked to familial amyotrophic lateral sclerosis (ALS), and reduced VAPB levels are observed in sporadic ALS patients.
- The precise mechanisms by which Vap dysfunction contributes to motor neuron degeneration remain unclear.
- Vap proteins are involved in various cellular functions, but their specific role in neuronal health is under investigation.
Purpose of the Study:
- To investigate the role of Vap in neuronal function and its potential contribution to ALS pathogenesis.
- To elucidate the interaction between Vap and the Down syndrome cell adhesion molecule (Dscam) in neurons.
- To understand how Vap influences the axonal localization and function of Dscam.
Main Methods:
- Utilized Drosophila melanogaster as a model organism to study Vap and Dscam interactions.
- Employed genetic loss-of-function approaches to analyze Vap's role in Dscam trafficking.
- Investigated the physical interaction between Vap and specific Dscam isoforms.
Main Results:
- Demonstrated that Vap physically interacts with Dscam, specifically isoforms containing TM2 sequences.
- Showed that Vap is essential for the axonal localization of TM2-containing Dscam isoforms.
- Found that Vap loss-of-function suppresses Dscam gain-of-function phenotypes related to axon development.
Conclusions:
- Vap plays a critical role in the selective axonal transport of proteins, including Dscam, within neurons.
- Disruption of Vap-mediated axonal transport may underlie motor neuron degeneration observed in ALS.
- This study provides new insights into the molecular mechanisms linking VAPB dysfunction to ALS pathology.
