Trk C signaling is required for retinal progenitor cell proliferation

Although neurotrophin actions in the survival of specific retinal cell type s have been identified, the biological functions for neurotrophin-3 (NT-3) in early retinal development remain unclear. Having localized NT-3 and trk C expression at early developmental stages when retinal neuroepithelial pro genitor cells predominate, we sought to modulate NT-3 signaling in these ce lls by overexpressing a truncated isoform of the NT-3 receptor, trk C. We h ave demonstrated that this non-catalytic receptor can inhibit NT-3 signalin g when coexpressed with the full-length kinase-active trk C receptor. Using a replication-deficient retrovirus to ectopically express the truncated tr k C receptor to limited numbers of progenitor cells in ovo, we examined the effects of disrupted trk C signaling on the proliferation or differentiati on of retinal cells. Clones expressing truncated trk C exhibited a 70% redu ction in clone size, compared with clones infected with a control virus, in dicating that inhibition of trk C signaling decreased the clonal expansion of cells derived from a single retinal progenitor cell. Additionally, impai red NT-3 signaling resulted in a reduction of all retinal cell types, sugge sting that NT-3 targets retinal precursor cells rather than differentiated cell types. BrdU labeling studies performed at E6 indicate that this reduct ion in cell number occurs through a decrease in cell proliferation. These s tudies suggest that NT-3 is an important mitogen early in retinal developme nt and serves to establish the size of the progenitor pool from which all f uture differentiated cells arise.