p75-NGFR and TNFR1 Interact and Cooperate During the Sympathetic Nervous System Development

During development, components of the nervous system are overproduced and then refined to achieve optimal connectivity and functionality. During this refinement process, excess neurons are weakened and eliminated, while others are strengthened and stabilized. The molecular basis for these refinement decisions remains unclear. This thesis examines how TNFR family members coordinate their activity to antagonize NGF-TrkA signaling in order to regulate neuronal cell death, axon growth, and cell size during development. First, the closely related TNFR family members, p75-NGFR and TNFR1, and their cognate ligands, BDNF and TNF, are expressed in sympathetic ganglia. In vitro, p75-NGFR and TNFR1 act cooperatively to countermand NGF-TrkA trophic signaling in order to cause ligand-initiated axon growth inhibition. However, such concurrent availability of the two receptors is required to cause cell death initiated by BDNF, but not by TNFα. Further, using co-immunoprecipitation and bimolecular fluorescence complementation (BiFC) assays, these receptors are shown to interact on the cellular surface. In vivo, this codependence does not appear to be necessary for developmental cell death, but is required for regulation of sympathetic soma size and proper axon patterning during target innervation. Taken together, these findings suggest cooperativity between p75-NGFR and TNFR1 in mediating a range of developmental processes including neuronal morphology regulation.