Axon-dendrite and apical-basolateral sorting in a single neuron.

Monique Lillis, Nathan J Zaccardi, Maxwell G Heiman

Genetics 2022 May 05

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Cells are highly organized machines with functionally specialized compartments. For example, membrane proteins are localized to axons or dendrites in neurons and to apical or basolateral surfaces in epithelial cells. Interestingly, many sensory cells-including vertebrate photoreceptors and olfactory neurons-exhibit both neuronal and epithelial features. Here, we show that Caenorhabditis elegans amphid neurons simultaneously exhibit axon-dendrite sorting like a neuron and apical-basolateral sorting like an epithelial cell. The distal ∼5-10 µm of the dendrite is apical, while the remainder of the dendrite, soma, and axon are basolateral. To determine how proteins are sorted among these compartments, we studied the localization of the conserved adhesion molecule SAX-7/L1CAM. Using minimal synthetic transmembrane proteins, we found that the 91-aa cytoplasmic tail of SAX-7 is necessary and sufficient to direct basolateral localization. Basolateral localization can be fully recapitulated using either of 2 short (10-aa or 19-aa) tail sequences that, respectively, resemble dileucine and Tyr-based motifs known to mediate sorting in mammalian epithelia. The Tyr-based motif is conserved in human L1CAM but had not previously been assigned a function. Disrupting key residues in either sequence leads to apical localization, while "improving" them to match epithelial sorting motifs leads to axon-only localization. Indeed, changing only 2 residues in a short motif is sufficient to redirect the protein between apical, basolateral, and axonal localization. Our results demonstrate that axon-dendrite and apical-basolateral sorting pathways can coexist in a single cell, and suggest that subtle changes to short sequence motifs are sufficient to redirect proteins between these pathways. © The Author(s) 2022. Published by Oxford University Press on behalf of Genetics Society of America.