Trk C signaling is required for retinal progenitor cell proliferation.
Although neurotrophin actions in the survival of specific retinal cell types 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 progenitor cells predominate, we sought to modulate NT-3 signaling in these cells by overexpressing a truncated isoform of the NT-3 receptor, trk C. We have demonstrated that this non-catalytic receptor can inhibit NT-3 signaling when coexpressed with the full-length kinase-active trk C receptor. Using a replication-deficient retrovirus to ectopically express the truncated trk C receptor to limited numbers of progenitor cells in ovo, we examined the effects of disrupted trk C signaling on the proliferation or differentiation of retinal cells. Clones expressing truncated trk C exhibited a 70% reduction in clone size, compared with clones infected with a control virus, indicating that inhibition of trk C signaling decreased the clonal expansion of cells derived from a single retinal progenitor cell. Additionally, impaired NT-3 signaling resulted in a reduction of all retinal cell types, suggesting that NT-3 targets retinal precursor cells rather than differentiated cell types. BrdU labeling studies performed at E6 indicate that this reduction in cell number occurs through a decrease in cell proliferation. These studies suggest that NT-3 is an important mitogen early in retinal development and serves to establish the size of the progenitor pool from which all future differentiated cells arise.
Das
I
I
Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021, USA.
Sparrow
J R
JR
Lin
M I
MI
Shih
E
E
Mikawa
T
T
Hempstead
B L
BL
D000818:Animals; D002454:Cell Differentiation; D002455:Cell Division; D002465:Cell Movement; D002642:Chick Embryo; D004789:Enzyme Activation; D005822:Genetic Vectors; D020933:Neurotrophin 3 / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D020812:Receptor, trkC / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012160:Retina / Q000166:cytology / Q000196:embryology*; D013234:Stem Cells / Q000166:cytology*; D014162:Transfection
D020933:Neurotrophin 3; D012333:RNA, Messenger; D020812:Receptor, trkC