A conserved Arf-GEF modulates axonal integrity through RAB-35 by altering neuron-epidermal attachment

Area of Science:

• Neurobiology
• Cell Biology
• Mechanobiology

Background:

• Sensory neurons in the skin are vulnerable to mechanical strain.
• The skin's neuroprotective mechanisms and molecular pathways are not fully understood.
• UNC-70/β-spectrin and RAB-35 are known to stabilize neuron-epidermal attachments in *C. elegans*.

Purpose of the Study:

• To identify novel molecular regulators of axonal integrity within the skin.
• To elucidate the mechanisms by which the skin maintains neuronal structure under mechanical stress.

Main Methods:

• Forward genetic screen in *C. elegans* to identify genes affecting axonal maintenance.
• Analysis of AGEF-1a function in the skin.
• Investigating the interaction between AGEF-1a and RAB-35.
• Testing the functional conservation of AGEF-1a using its human ortholog, BIG2.

Main Results:

• Identified AGEF-1a, a guanine nucleotide exchange factor (GEF), as crucial for axonal maintenance in the skin.
• AGEF-1a functions in the skin to regulate the integrity of embedded axons.
• AGEF-1a interacts with epidermal RAB-35, facilitating its activation and modulating neuron-epidermal attachments.
• The human ortholog of AGEF-1a, BIG2, can functionally replace AGEF-1a, indicating conserved function.

Conclusions:

• AGEF-1a is a key component of the molecular machinery that maintains neuron-epidermal attachments and axonal integrity in the skin.
• The AGEF-1a-RAB-35 pathway in the skin is essential for protecting sensory neurons from mechanical damage.
• This pathway is conserved across species, highlighting its fundamental importance.