The VAPB Axis Precisely Coordinates the Timing of Motoneuron Dendritogenesis in Neural Map Development

Area of Science:

• Neuroscience
• Cell Biology
• Developmental Biology

Background:

• Spatiotemporal dendritic patterning in Drosophila motoneurons is crucial for neural circuit formation.
• Mechanisms regulating the temporal aspects of dendritic development are largely unknown.
• Cdc42 GTPase was previously identified as a key actin modulator in this process.

Purpose of the Study:

• To identify upstream factors that activate Cdc42 in Drosophila motoneurons.
• To elucidate the signaling pathway linking extracellular cues to intracellular Cdc42 activation.
• To investigate the role of VAMP-associated protein 33 (Vap33) in temporal regulation of dendritic development.

Main Methods:

• Single-cell genetics in Drosophila.
• Förster resonance energy transfer (FRET)-based imaging.
• Biochemical techniques to analyze protein interactions and activation states.

Main Results:

• The guanine nucleotide exchange factor Vav is recruited to the plasma membrane by the Eph receptor tyrosine kinase, leading to Cdc42 activation.
• VAMP-associated protein 33 (Vap33), an Eph ligand, is secreted non-cell-autonomously and induces Eph receptor autophosphorylation.
• Vap33 transitions from an ER-resident protein to an extracellular cue, signaling the timing of Cdc42 activation.

Conclusions:

• Vav, Eph receptor, and Vap33 form a signaling axis that temporally regulates Cdc42 activation for dendritic patterning.
• Extracellular Vap33 acts as a temporal cue in motor neuron development.
• The conserved human ortholog VAPB is implicated in motor neuron diseases (ALS8, SMA), highlighting the clinical relevance of this pathway.