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J. Cell Biol.,
Volume 140, Number 4, February 23, 1998 911-923
Center for Neuronal Survival, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada H3A 2B4
Abstract. To determine whether the p75 neurotrophin
receptor (p75NTR) plays a role in naturally occurring
neuronal death, we examined neonatal sympathetic
neurons that express both the TrkA tyrosine kinase receptor and p75NTR. When sympathetic neuron survival is maintained with low quantities of NGF or KCl,
the neurotrophin brain-derived neurotrophic factor
(BDNF), which does not activate Trk receptors on
sympathetic neurons, causes neuronal apoptosis and
increased phosphorylation of c-jun. Function-blocking antibody studies indicate that this apoptosis is due to
BDNF-mediated activation of p75NTR. To determine
the physiological relevance of these culture findings, we
examined sympathetic neurons in BDNF
/ and
p75NTR/ mice. In BDNF/ mice, sympathetic
neuron number is increased relative to BDNF+/+ littermates, and in p75NTR/ mice, the normal period
of sympathetic neuron death does not occur, with neuronal attrition occurring later in life. This deficit in apoptosis is intrinsic to sympathetic neurons, since cultured p75NTR/ neurons die more slowly than do their
wild-type counterparts. Together, these data indicate
that p75NTR can signal to mediate apoptosis, and that
this mechanism is essential for naturally occurring sympathetic neuron death.
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