Sunday, March 16, 2025
3/16/2025
PROJECT SUMMARY Proper formation of the head and face involves coordination of interactions among multiple tissues, including the cranial nerves and mesenchyme, with aberrant interactions leading to cranio- and/or orofacial anomalies. These abnormalities account for one-third of all birth defects, place a substantial financial burden on our healthcare system, and are the primary cause of infant mortality. Thus, a comprehensive understanding of craniofacial development that incorporates nerve-tissue interactions in a holistic approach is essential to overcome the current challenges in treatment of diseases and disorders affecting the head and face. Many cranial nerves transmit somatosensory information and possess neuronal cell bodies and glia within cranial ganglia, which arise from the coalescence and differentiation of neural crest cells (NCCs) and placode cells (PCs). The appearance of these ganglia, and the nerves to which they contribute, typically precedes that of their target tissues, strongly implicating innervation in the context of target development. Notably, the trigeminal ganglion (TG) mediates the majority of facial sensations due to its association with cranial nerve V, which is uniquely positioned in the head to influence cranial cartilage and bone development due to the tissues through which it traverses. Prior studies, including work by our lab, have shown the importance of NGF/TrkA signaling in TG axon outgrowth and target tissue innervation. Intriguingly, this pathway has also been implicated in trunk long bone development, maintenance, and repair, but this function for NGF/TrkA signaling has not been explored in the context of cranial cartilage and bone development. Moreover, our new studies reveal remarkable deficits in cranial bone upon perturbation of the PC component of the TG, a cell type that does not make this tissue, further underscoring the importance of nerve-tissue interactions during development. However, the processes by which TG innervation actively orchestrates target development and maintenance remain a significant gap in our knowledge of craniofacial development. Herein, we will interrogate how unique nerve (TG)-target tissue (cranial mesenchyme) interactions are required for the TG and its nerves to direct cranial cartilage and bone development through pioneering studies in the chick embryo in the following Specific Aims: 1) determine the role of NGF/TrkA signaling in embryonic cranial cartilage and bone development and 2) define how TG innervation directs target tissues to form cartilage and bone. Our proposed research is innovative because it employs a systems-level, multidisciplinary approach involving embryology, molecular cell biology, and transcriptomics, with the goal of generating a new model to study nerve-target tissue interactions. These results will significantly advance our knowledge of the molecular mechanisms underscoring TG nerve-tissue interactions directing formation of the head, and, collectively, the etiology and therapeutic treatment of cranial nerve disorders and diseases arising from aberrant NCC and PC development.
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