BalancebetweenBcl-2(anti-
apoptotic) and Bax/Bak
controls initiation
Released cytochrome c
binds APAF-1, which
binds and activates
procaspase 9
Extrinsic
pathway
Due to activation of Death
Receptors by external
ligands, e.g. TNF
Death receptors have intracellular Death
Domains which bind adaptor proteins and
procaspase 8 into a Death Inducing
Signalling Complex (DISC), thus releasing
active caspase 8
Role in development
Cell death is critical
Loss of caspase 9 leads to exencephaly
Why cell death?
PCD occurs in all tissues in
development and throughout life
Why? (see Raff 1996, Cell v86,
p173, for great discussion)
Size control
Most tissues are
inter-dependent, you
must keep things in
proportion
Axons receive ‘trophic
support’ from their
targets (and vice-versa)
Removal of
transient
structures
E.g. subplate neurons in
cortex, Ti1 axons in
grasshopper limb: both are
scaffolds for later axons and
die once their job is done
Functional
tuning -
matching
Elimination of synapses
Viktor Hamburger 1900-2001 Student of
Hans Spemann, mentor to Levi-Montalcini
and Stanley Cohen, discoverers of NGF.
What factors
underlie this
interdependence?
Neurotrophins
lack of NGF
promotes survival
and in some
contexts its
absence actively
promotes cell
death.
Over expression of
p75NTR in
Trk-expressing cells
drives cell death
Lowered expression
of p75NTR promotes
cell survival
Binding of a neurotrophin to
p74NTR in the absence of its
appropriate Trk drives death
p75NTR acts as a complex ‘death
switch’ to tune neuronal survival
to innervation of appropriate
targets
Because of its 'death switch' properties,
P75NTR is known as a 'dependence receptor'
There are now a large group of ‘dependence
receptors’ defined by their ability to induce
PCD in the absence of their respective
ligands via caspase- dependent cleavage of
their ICDs to release, poorly- defined,
proapoptotic peptides
Interestingly, many of the identified
dependence receptors are known guidance
receptors (also include EphA4 and TrkC)
DCC = Deleted in Colon Cancer
Electrical activity can also
modify response to death
signals through activation of
neurotrophin expression
Its not all about cells dying
The pruning back of initially
exuberant growth is a widespread
feature of NS development
e.g. cortico-spinal and
cortico-collicular projections
are initially similar, but are
differentially pruned
Many features of pruning are
shared with Wallerian
degeneration and with
apoptosis, including
Cell
fragmentation
Clearing by
phagocytosis
Led to the speculation
that PCD pathways may
be involved in both...
Local caspase
activity directs
pruning
DRONC is the caspase9 (ie initiator
caspase) equivalent in drosophila
Dendrites of local sensory neurons are pruned by
local degeneration, involving branch severing,
blebbing and fragmentation cf. Wallerian deg
Bloackade of DRONC (Lof
or DN) blocks pruning
A reporter of caspase activation
(based on PARP, an Effector caspase
substrate), shows local activity at
sites of branch severing
Evidence suggests caspases do not
initiate severing of branches but are
involved in the subsequent process of
engulfment by phagocytes