Halmi, C. | Search bioRxiv

bioRxiv2025

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

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.

developmental biology↗

bioRxiv2024

N-cadherin facilitates trigeminal sensory neuron outgrowth and target tissue innervation

The trigeminal ganglion emerges from the condensation of two distinct precursor cell populations, cranial placodes and neural crest. While its dual cellular origin is well understood, the molecules underlying its formation remain relatively obscure. Trigeminal ganglion assembly is mediated, in part, by neural cadherin (N-cadherin), which is initially expressed by placodal neurons and required for their proper coalescence with neural crest cells. Axon outgrowth first occurs from placodal neurons, but as gangliogenesis proceeds, neural crest cells also differentiate into N-cadherin-expressing neurons, and both extend axons toward targets. However, the role of N-cadherin in axon outgrowth and target innervation has not been explored. Our data show that N-cadherin knockdown in chick trigeminal placode cells decreases trigeminal ganglion size, nerve growth, and target innervation in vivo, and reduces neurite complexity of neural crest-derived neurons in vitro. Furthermore, blocking N-cadherin-mediated adhesion prevents axon extension in most placodal neurons in vitro. Collectively, these findings reveal cell- and non-cell autonomous functions for N-cadherin, highlighting its critical role in mediating reciprocal interactions between neural crest- and placode-derived neurons throughout trigeminal ganglion development.

developmental biology↗