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The Journal of Neuroscience, July 1, 1999, 19(13):5393-5408
Functionally Antagonistic Interactions between the TrkA and p75
Neurotrophin Receptors Regulate Sympathetic Neuron Growth and Target
Innervation
Judi
Kohn1,
Raquel S.
Aloyz1,
Jean G.
Toma1,
Mary
Haak-Frendscho2, and
Freda D.
Miller1
1 Centre for Neuronal Survival, Montréal
Neurological Institute, McGill University, Montréal,
Québec, Canada, H3A 2B4, and 2 Department of
Immunology, Promega Corporation, Madison, Wisconsin 53711
In this report, we provide evidence that NGF and BDNF have
functionally antagonistic actions on sympathetic neuron growth and
target innervation, with NGF acting via TrkA to promote growth and BDNF
via p75NTR to inhibit growth. Specifically, in cultured sympathetic
neurons that themselves synthesize BDNF, exogenous BDNF inhibits and
function-blocking BDNF antibodies enhance process outgrowth. Both
exogenous and autocrine BDNF mediate this effect via p75NTR because (1)
BDNF does not inhibit growth of neurons lacking p75NTR, (2)
function-blocking p75NTR antibodies enhance NGF-mediated growth, and
(3) p75NTR / sympathetic neurons grow more
robustly in response to NGF than do their wild-type counterparts. To
determine the physiological relevance of this functional antagonism, we
examined the pineal gland, a well defined sympathetic target organ.
BDNF is present in the pineal gland during target innervation, and
incoming sympathetic axons are p75NTR positive. Moreover, the pineal
glands of BDNF+/ and BDNF/
mice are hyperinnervated with sympathetic fibers, and tyrosine hydroxylase (TH) levels are elevated. Increased tyrosine hydroxylase is
also observed in the BDNF+/ carotid artery,
another sympathetic neuron target. Thus, BDNF, made by sympathetic
neurons and/or their target organs, acts via p75NTR to antagonize
NGF-mediated growth and target innervation, suggesting that sympathetic
target innervation is determined by the balance of positively and
negatively acting neurotrophins present in developing and potentially
mature targets.
Key words:
nerve growth factor; brain-derived neurotrophic factor; sympathetic neurons; target innervation; neurotrophin receptor; TrkA; p75NTR; pineal gland
Copyright © 1999 Society for Neuroscience 0270-6474/99/19135393-16$05.00/0
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