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The Journal of Neuroscience, September 15, 1999, 19(18):7889-7900
Rapid Nuclear Responses to Target-Derived Neurotrophins Require
Retrograde Transport of Ligand-Receptor Complex
Fiona L.
Watson1, 2, 4,
Heather M.
Heerssen1, 2, 4,
Daniel B.
Moheban1, 2, 4,
Michael Z.
Lin5,
Claire M.
Sauvageot1, 2, 3,
Anita
Bhattacharyya1, 3, 4,
Scott L.
Pomeroy5, and
Rosalind A.
Segal1, 2, 4
1 Program in Neuroscience, 2 Department of
Neurobiology, and 3 Department of Microbiology and
Molecular Genetics, Harvard Medical School, Boston, Massachusetts
02115, 4 Department of Pediatric Oncology, Dana-Farber
Cancer Institute, Boston, Massachusetts 02115, and
5 Division of Neuroscience, Department of Neurology,
Children's Hospital, Boston, Massachusetts 02115
Target-derived neurotrophins initiate signals that begin at nerve
terminals and cross long distances to reach the cell bodies and
regulate gene expression. Neurotrophin receptors, Trks,
themselves serve as retrograde signal carriers. However, it is not yet
known whether the retrograde propagation of Trk activation reflects movement of Trk receptors from neurites to cell bodies or reflects serial activation of stationary Trk molecules. Here, we show that neurotrophins selectively applied to distal neurites of sensory neurons
rapidly induce phosphorylation of the transcription factor cAMP
response element-binding protein (CREB) and also cause a slower
increase in Fos protein expression. Both nuclear responses require
activation of neurotrophin receptors (Trks) at distal nerve endings and
retrograde propagation of Trk activation to the nerve cell bodies.
Using photobleach and recovery techniques to follow biologically
active, green fluorescent protein (GFP)-tagged BDNF receptors
(TrkB-GFP) in live cells during retrograde signaling, we show that
TrkB-GFP moves rapidly from neurites to the cell bodies. This rapid
movement requires ligand binding, Trk kinase activity, and intact
axonal microtubules. When they reach the cell bodies, the activated
TrkB receptors are in a complex with ligand. Thus, the retrograde
propagation of activated TrkB from neurites to cell bodies, although
rapid, reflects microtubule-dependent transport of
phosphorylated Trk-ligand complexes. Moreover, the relocation
of activated Trk receptors from nerve endings to cell bodies is
required for nuclear signaling responses. Together, these data support
a model of retrograde signaling whereby rapid vesicular transport of
ligand-receptor complex from the neurites to the cell bodies mediates
the nuclear responses.
Key words:
retrograde signaling; retrograde transport; c-fos; neurotrophin; Trk; DRG
Copyright © 1999 Society for Neuroscience 0270-6474/99/19187889-12$05.00/0
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