Mechanistic insights into cellular and molecular regulation of trigeminal ganglion development

Organisms frequently rely upon cell-cell interactions to build various structures throughout their body plan. One outstanding example of this is the formation of the cranial trigeminal ganglion, a tissue that consists of neurons arising from both neural crest and placode cells. The central question of this research is to understand how trigeminal ganglion neurons coordinate, in space and time, their initial formation, and extension of axons to target tissues, to detect sensations. To address this question, an innovative, multidisciplinary approach will be taken that spans the single cell to whole embryo. Results from these experiments will shed light on processes underlying trigeminal ganglion neurodevelopment, providing immediate relevance for the identification of fundamental mechanisms controlling intercellular interactions and neuron formation during development and the maintenance of adult tissues. The research produced through this project will have broad impacts on our understanding of normal neurodevelopment, offering insight into how abnormalities underlie deficits and promoting scientific progress and national health. It will also provide preK-12 and undergraduate STEM education and teacher training activities through outreach to high school students, undergraduates, and teachers, along with giving experiential research opportunities to undergraduate and graduate students. As such, this project advances NSF’s priorities in Biotechnology by developing an American STEM workforce that is globally competitive in STEM education and biotechnology. The objective of this proposal is to uncover mechanisms by which sensory neurons of the cranial trigeminal ganglion extend axons to their target tissues using the chick as a model system. The trigeminal ganglion is generated by interactions between two key precursors, placode cells and neural crest cells, with the former differentiating into neurons before the latter. While the dual cellular origin of the trigeminal ganglion has been known for years, the molecular mechanisms mediating trigeminal ganglion development remain obscure. The Taneyhill lab’s publications have begun to bridge this knowledge gap by defining molecules involved in initial trigeminal ganglion assembly and later axon outgrowth, including N-cadherin (N-cad), which is expressed by all trigeminal ganglion neurons regardless of cellular origin. Their results show integrin-extracellular matrix (ECM) and N-cad-N-cad interactions respectively orchestrate axon outgrowth of initial placode cell-derived “pioneer” neurons and later “follower” neurons arising from placode and neural crest cells. The lab also discovered that N-cad physically interacts with TrkA, a cell surface receptor in neural crest-derived trigeminal ganglion neurons that is crucial for neuron survival. Further, recent findings point to a novel role for N-cad in mediating TrkA glycosylation and transit inside the cell. Building on these results, the aims of the proposed research are to 1) define N-cad-independent mechanisms underlying integrin-ECM interactions that drive trigeminal ganglion pioneer axon extension; 2) determine the function of N-cad in controlling TrkA glycosylation and trafficking; and 3) characterize, for the first time, the trigeminal ganglion glycoproteome. These aims will be achieved using biochemistry; live imaging; molecular perturbation assays; glycoproteomics; and immunohistochemistry coupled with high-resolution confocal microscopy. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria. NSF Award ID: 2540444 | Program: 01002627DB NSF RESEARCH & RELATED ACTIVIT | Principal Investigator: Lisa Taneyhill | Institution: University of Maryland, College Park, COLLEGE PARK, MD | Award Amount: $799,892 View on NSF Award Search: https://www.nsf.gov/awardsearch/show-award/?AWD_ID=2540444 View on Research.gov: https://www.research.gov/awardapi-service/v1/awards/2540444.html