Download Slide 1

Terminal deoxynucleotidyl transferase dUTP nick end labeling
Dependency on Synaptic Target
FIGURE 7.15 The high-affinity NGF receptor was discovered through a series of disparate
observations. A. NGF was found to elicit protein phosphorylation in PC12 cells. B. The
oncogene in a cancer cell line was found to be a transmembrane receptor tyrosine kinase
(RTK). C. The messenger RNA for this RTK was found in extremely high levels in DRG
neurons. D. When this RTK, called p140, was eliminated from PC12 cells, they became
unresponsive to NGF. (Adapted from Maher, 1988; Martin-Zanca et al., 1986; MartinZanca
et al., 1990; Loeb et al., 1991)
FIGURE 7.16 The NGF signal can be transduced at the tips of growing neuronal processes.
Sympathetic neurons were placed in a special tissue culture system that permitted the cell
bodies and neurites to be bathed in different media. (Left) Most neurons died when grown
in the absence of NGF for 30 hours. (Right) Neurons could be kept alive by adding NGF only
to the compartments with growing neurites. In both cases, an antibody against NGF was
added to the central compartment to prevent activation of TrkA. (Adapted from Campenot,
1977, 1982; MacInnis and Campenot, 2002)
FIGURE 7.27 The molecular state of a neuron
that permits it to survive or leads it to death.
(Left) The
living cell contains mitochondria that are
preserved in a nonpermeable state due to the
presence of an antiapoptotic regulator, Bcl-2.
A second anti-apoptotic regulator, Bcl-x,
complexes with Apaf-1, preventing the
activation of caspase-9. Bcl-x also binds to a
pro-apoptotic regulator, Bax, and prevents it
from influencing the mitochondrion. A
different pro-apoptotic regulator, Bad, is
inactive, having been phosphoryated by
neurotrophin-elicited kinase activity. IAP binds
to pro-caspase-9, and this also serves to
prevent activation. A nuclease that is
responsible for DNA fragmentation, caspaseactivated deoxyribonuclease (CAD), is bound
by its inhibitor, ICAD. (Right) In dying neurons,
Bad becomes active when it is
dephosphorylated, and it binds to Bcl-x. This
permits Bax to associate with the
mitochondrion, leading to the release of
cytochrome c, AIF, and Smac. It also permits
Apaf-1 to form an apoptosome with cyt c,
process caspase-9, and activate caspase-3.
Smac binds to IAP, which also permits the
processing of pro-caspase-9. One target of
caspase-3 isICAD, leading to the release of
CAD, and the fragmentation of DNA. In a
caspase-independent pathway, AIF also enters
the nucleus and fragments DNA.
FIGURE 7.29 Blocking synaptic transmission
prevents normal motor neuron cell death. A.
Neuromuscular transmission can be blocked by
applying curare onto the chorioallantoic
membrane of chick embryos. B. In control
animals, over 30% of motor neurons die after
embryonic day 5. When animals are treated with
curare from E6-9, the magnitude of normal cell
death is greatly diminished. (Panel B adopted
from Pittman and Oppenheim, 1979)
FIGURE 7.30 Electrical activity enhances the survival of
embryonic cortex neurons by way of a neurotrophic
signal. When the cultures are depolarized by adding KCl
to the culture media, calcium enters the neurons, and
the level of BDNF expression increases, leading to
greater neuron survival compared to control media. The
trophic influence of depolarization is eliminated by
adding a function-blocking anti-BDNF antibody to the
growth medium. (Adopted From Ghosh et al., 1994)
FIGURE 7.31 Afferent innervation regulates neuron survival in a chick central auditory
nucleus. A. Auditory neurons from the cochlea innervate the nucleus magnocellularis (NM)
in the chick auditory brain stem. The removal of a cochlea (right) completely denervates
NM neurons on the ipsilateral side. B. When a cochlea is removed at embryonic day 2 (E2),
about 30% of NM neurons are lost during the ensuing two weeks, although cell death does
not begin until E10. When the cochlea is removed at posthatch day 14, about 25% of
neurons die within two days. In adults, cochlear ablation results in the loss of only about 5%
of NM neurons. (Adapted from Parks, 1979; Born and Rubel, 1985)