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Neurotrophin (NT)-3, one of the members of the neurotrophin family, regulates multiple events in the development and maturation of the peripheral nervous system (PNS) and the central nervous system (CNS). TrkC, the main receptor for NT-3 is expressed in the PNS, CNS, and other tissues.1 Full-length TrkC (TrkC.FL) is a approximately 150-kDa type 1 receptor tyrosine kinase protein that relays trophic signals. By alternative splicing, the trkC locus can generate truncated receptor isoforms such as TrkC.T1, which lacks the kinase domain and has a unique short intracellular domain. Overexpression of TrkC.T1 causes defects in the nervous system.2 Neurodegeneration can ensue because TrkC.T1 acts as a dominant-negative receptor of TrkC.FL or because TrkC.T1 sequesters NT-3.3,4 These mechanisms are indirect and do not require TrkC.T1 to signal. However, we recently showed that truncated Trk receptors can signal in a ligand-dependent manner, leading to the activation of Rac1 GTPase, the ruffling of the plasma membrane, and the formation of cellular protrusions.5–7 To further study the biological function of TrkC.T1 in vivo, we took advantage of the observation that the TrkC.T1 isoform is significantly upregulated during the early phase of glaucoma. TrkC.T1 upregulation was selective for glaucoma; it was not seen in optic nerve axotomy.8 We sought to determine whether TrkC.T1 was relevant to neurodegeneration in glaucoma. Glaucoma is a group of optic nerve neuropathies characterized by the chronic and progressive death of retinal ganglion cells (RGCs). Elevated intraocular pressure (IOP) is a major risk factor.9 Although the etiology of RGC death in glaucoma is multifactorial, a key contributor is the production by retinal glia of factors that are neurotoxic to RGCs. Two known neurotoxic factors are tumor necrosis factor-α (TNF-α)10–13 and α2-macroglobulin (α2m).14 These factors are secreted by the retinal glia in normal eyes and in glaucomatous eyes. However, the mechanism by which the retinal glia can finely regulate baseline secretion versus upregulated secretion of proteins that cause progressive RGC death in a chronic condition such as glaucoma is unknown.15 Therefore, we explored the mechanisms that regulate the production of neurotoxic factors that cause RGC death in glaucoma. Here we provide genetic, anatomic, and pharmacologic evidence correlating the glaucoma-induced expression of TrkC.T1 and the production of TNF-α in activated retinal glia or Muller cells leading to RGC death over time. Together, these data suggest a paracrine mechanism whereby high IOP causes early upregulation of TrkC.T1, which in turn regulates TNF-α production, causing glaucomatous RGC death. This work provides new evidence on the relevance of truncated neurotrophin receptors in disease and potentially validates TrkC.T1 as a target for glaucoma therapy.