Multiple glycoforms of TrkA interact with N-cadherin during trigeminal ganglion neurodevelopment

Abstract

The trigeminal ganglion is a component of the sensory nervous system that arises from neural crest and placode cells. The dual origin of the trigeminal ganglion leads to a heterogenous neuronal population that transmits somatosensory information from the face back to the brain. Proper trigeminal ganglion development relies, in part, on neurotrophic signaling, including interactions between Nerve Growth Factor and its cognate receptor, Tropomyosin receptor kinase A (TrkA), a receptor tyrosine kinase. Post-translational modifications, including glycosylation, play a crucial role in the ability of TrkA to reach the plasma membrane, yet the specific glycan profile and functional relevance of these modifications have not been characterized in sensory neurons in vivo. Here, we sought to characterize the different glycosylation events occurring on TrkA during trigeminal ganglion neurodevelopment. We discovered that multiple glycoforms of TrkA exist that correlate to partially and fully mature versions of the protein reported in vitro. Furthermore, we discovered that TrkA interacts with a cell adhesion molecule, N-cadherin, on membranes of trigeminal neurons, both in the cell bodies and axons. Based on the size of the TrkA bands that interact with N-cadherin, our results suggest these interactions are occurring both on the plasma membrane and intracellularly on the membrane of organelles. While interactions between receptor tyrosine kinases and cadherins have been shown in other contexts, our findings are the first to identify such an interaction in the trigeminal ganglion and suggest an important role for coordination between neurotrophic signaling and cell adhesion for proper neurodevelopment, both during TrkA protein maturation and during receptor tyrosine kinase signaling. Given that aberrant receptor tyrosine kinase and cadherin signaling is commonly implicated in neurodevelopmental disorders and cancer, understanding how these interactions are established during normal development may provide additional insight into their dysregulation during disease.