Ontogeny of Vagal Sensory Cell Types and Trophic Factor Sensitivity

Vagal sensory neurons located in the nodose ganglion provide a direct line of communication from the gut to the brain. Information, such as stomach stretch or the presence of ingested nutrients in the intestine, is conveyed to the caudal medulla via specialized cell types that express unique marker genes. Here, we leverage vagal cell type marker genes identified in adult mice to determine when specialized vagal subtypes arise developmentally, as well as the factors that shape their growth and target innervation. Initial sequencing and pathway analysis comparing early postnatal to adult nodose ganglia identified an enrichment of differentially expressed genes (DEGs) related to axon growth and guidance, synaptic strengthening, and DEGs downstream of brain derived neurotrophic factor (BDNF). Subsequent experiments performed to screen for trophic factor sensitivity revealed that both BDNF and glial cell derived neurotrophic factor (GDNF) robustly stimulate neurite outgrowth from early postnatal nodose ganglion explants in vitro. Anatomical examination of whole-body trophic factor expression in perinatal mice revealed that BDNF is expressed by neurons of the nodose ganglion itself, while GDNF is expressed by developing intestinal smooth muscle cells. Thus, BDNF may support vagal neurons as a locally derived trophic factor, while GDNF may act as a target derived trophic factor supporting the growth of vagal sensory processes at distal innervation sites in the gut. Consistent with this, expression of the GDNF receptor, Gfra1, was enriched in vagal afferent cell types that project to the gastrointestinal tract. The BDNF receptor, Ntrk2, was expressed by the majority vagal sensory neurons, irrespective of cell type. Lastly, spatial mapping of genetic markers in the nodose ganglion demonstrates that defined vagal cell types begin to emerge as early as embryonic day 13, even as sensory neurons continue to grow to reach gastrointestinal targets. Despite the early onset of expression for some cell type marker genes, expression patterns of many individual cell type markers appear largely immature in prenatal life and mature considerably by the end of the first postnatal week. Together, the data support a role for GDNF in stimulating vagal sensory growth to gastrointestinal targets and establish a prolonged perinatal timeline for vagal sensory cell type maturation.