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Department of Cell Biology and Anatomy, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada T6G 2H7
According to the current theory of retrograde signaling, NGF binds to receptors on the axon
terminals and is internalized by receptor-mediated endocytosis. Vesicles with NGF in their lumina, activating
receptors in their membranes, travel to the cell bodies and initiate signaling cascades that reach the nucleus.
This theory predicts that the retrograde appearance of
activated signaling molecules in the cell bodies should
coincide with the retrograde appearance of the NGF
that initiated the signals. However, we observed that
NGF applied locally to distal axons of rat sympathetic neurons in compartmented cultures produced increased tyrosine phosphorylation of trkA in cell bodies/
proximal axons within 1 min. Other proximal proteins,
including several apparently localized in cell bodies,
displayed increased tyrosine phosphorylation within 5-15 min. However, no detectable 125I-NGF appeared
in the cell bodies/proximal axons within 30-60 min of
its addition to distal axons. Even if a small, undetectable fraction of transported 125I-NGF was internalized
and loaded onto the retrograde transport system immediately after NGF application, at least 3-6 min would be required for the NGF that binds to receptors on distal axons just outside the barrier to be transported to
the proximal axons just inside the barrier. Moreover, it
is unlikely that the tiny fraction of distal axon trk receptors located near the barrier alone could produce a
measurable retrograde trk phosphorylation even if
enough time was allowed for internalization and transport of these receptors. Thus, our results provide strong
evidence that NGF-induced retrograde signals precede
the arrival of endocytotic vesicles containing the NGF
that induced them. We further suggest that at least
some components of the retrograde signal are carried by a propagation mechanism.
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