R. Butowt et Cs. Von Bartheld, Sorting of internalized neurotrophins into an endocytic transcytosis pathway via the Golgi system: Ultrastructural analysis in retinal ganglion cells, J NEUROSC, 21(22), 2001, pp. 8915-8930
Subcellular pathways and accumulation of internalized radiolabeled neurotro
phins NGF, BDNF, and NT-3 were examined in retinal ganglion cells (RGCs) of
chick embryos by using quantitative electron microscopic autoradiography.
All three neurotrophins accumulated in endosomes and multivesicular bodies.
BDNF and NGF also concentrated at the plasma membrane, whereas NT-3 accumu
lated transiently in the Golgi system. The enhanced targeting of NT-3 to th
e Golgi system correlated with the anterograde axonal transport of this neu
rotrophin. Anterograde transport of NT-3, but not its internalization, was
significantly attenuated by the tyrosine kinase (trk) inhibitor K252a. Abol
ishment of trk activity with K252a shifted NT-3 (and BDNF) away from the Go
lgi system and into a lysosomal pathway, indicating that trk activity regul
ated sorting of the ligand-receptor complex. Cross-linking of neurotrophins
and immunoprecipitation with antibodies to the neurotrophin receptors p75,
trkA, trkB, and trkC showed that the large majority of exogenous, receptor
-bound NT-3 was bound to trkC in RGC somata, but during anterograde transpo
rt in the optic nerve most receptor-bound NT-3 was associated with p75, and
after arrival and release in the optic tectum transferred to presumably po
stsynaptic trkC. These results reveal remarkable and unexpected differences
in the intracellular pathways and fates of different neurotrophins within
the same cell type. They provide first evidence for an endocytic pathway of
internalized neurotrophic factors via the Golgi system before anterograde
transport and transcytosis. The results challenge the belief that after int
ernalization all neurotrophins are rapidly degraded in lysosomes.