p75-Mediated NF-B Activation Enhances the
Survival Response of Developing Sensory
Neurons to Nerve Growth Factor
Makoto Hamanoue,
1
Gayle Middleton, Sean Wyatt, Ellis Jaffray,
Ronald T. Hay, and Alun M. Davies
School of Biomedical Sciences, University of St. Andrews, Biomedical Science Building,
St. Andrews, Fife KY16 9AJ, Scotland
We have investigated whether the transcription factor
NF-B plays a role in regulating neuronal survival by
manipulating NF-B activation in the nerve growth factor
(NGF)-dependent sensory neurons of the embryonic mouse
trigeminal ganglion. Overexpression of either the p65 or
the p50 NF-B subunits resulted in NF-B activation and
promoted
in vitro
survival as effectively as NGF. Expres-
sion of a superrepressor IB-␣ protein prevented NF-B
activation in p65/p50-overexpressing neurons and caused
the neurons to die as rapidly as NGF-deprived neurons.
NGF treatment also activated NF-B, and preventing this
activation with superrepressor IB-␣ reduced the NGF
survival response. Antibodies that block binding of NGF to
the p75 receptor prevented NGF-induced NF-B activation
and reduced the NGF survival response to the same extent
as superrepressor IB-␣. Trigeminal neurons cultured
from
p65
؊/؊
embryos showed a reduced survival response
to NGF compared with neurons from wild-type embryos
and there was increased apoptosis of neurons in the
trigeminal ganglia of
p65
؊/؊
embryos
in vivo.
However, as
with p75-deficient sensory neurons, p65-deficient sensory
neurons showed a normal survival response to BDNF.
These results reveal a role for NF-B in regulating neuro-
nal survival during embryonic development and suggest
that in addition to the well-established Trk receptor tyro-
sine kinase signaling cascade, NGF enhances neuronal
survival by signaling via a p75-mediated pathway.
INTRODUCTION
NF-B is a ubiquitous transcription factor (Baldwin,
1996; Ghosh et al., 1998). In most cell types, it is present
as a heterodimer comprising p65 and p50 subunits that
is held in an inactive form in the cytosol by interaction
with a member of the IB family of inhibitory proteins
(Verma and Stevenson, 1997; Karin, 1998). NF-Bis
activated bythe phosphorylation and subsequentdegra-
dation of IB, which results in translocation of the
liberated NF-B to the nucleus where it induces tran-
scription of target genes. A wide variety of noxious
stimuli such as viral and bacterial infection, UV light,
ionizing radiation, and free radicals as well as a variety
of lymphokines and cytokines activate NF-B, which in
turn positively regulates the expression of genes that
mediate an acute inflammatory response (Baldwin,
1996; Baeuerle and Baichwal, 1997). The recent demon-
stration that NF-B activation suppresses apoptosis
induced by tumor necrosis factor (TNF) and various
genotoxic agents in lymphoid and fibroblast cell lines
(Beg and Baltimore, 1996; Van Antwerp et al., 1996;
Wang et al., 1996) and protects hippocampal neurons
against oxidative stress-induced apoptosis (Mattson et
al., 1997) together with the finding that there is massive
hepatocyte death in p65
Ϫ/Ϫ
mouse embryos (Beg et al.,
1995) indicates that NF-B also plays a role in regulating
cell survival.
In the nervous system, NF-B is not only involved in
mediating inflammatory responses (O’Neill and
Kaltschmidt, 1997) but is induced by several molecules
that play key roles in neural function and development.
For example, NF-B is induced by glutamate in cerebel-
lar granule cells (Guerrini et al., 1995; Kaltschmidt et al.,
1995) and by nerve growth factor (NGF) in Schwann
cells (Carter et al., 1996). Furthermore, there are marked
developmental changes in NF-B activation in various
brain regions of the mouse embryo (Schmidt-Ullrich et
al., 1996). These observations indicate that NF-B has
1
Present address: Department of Molecular Neurobiology, Institute
of DNAMedicine, JikeiUniversity, School of Medicine,3-25-8Nishish-
inbashi, Minatoku, Tokyo 105, Japan.
MCN
Molecular and Cellular Neuroscience
14, 28–40 (1999)
Article ID
mcne.1999.0770,
available online at http://www.idealibrary.com on
28
1044-7431/99 $30.00
Copyright
1999 by Academic Press
All rights of reproduction in any form reserved.