Chap. 21 Stem Cells, Cell Asymmetry, and Cell Death

1
Chap. 21 Stem Cells, Cell Asymmetry, and Cell
Death

• Topics
• Cell Death and Its Regulation

Goals

• Learn the basic mechanism of apoptosis and its
  regulation.
• Learn the basic roles of neurotrophins and
  apoptosis in wiring of the nervous system.
• Learn the functions of caspases in apoptosis.

2
Overview of Apoptosis
Apoptosis (programmed cell death) is a cell fate
that is essential in some developmental programs.
Apoptosis is highly regulated. It can be induced
by withdrawal of trophic factors, which signal
cells to stay alive. Alternatively, signals
(e.g., death signals like tumor
necrosis factor) trigger apoptosis. The
structural changes that occur during apoptosis
are morphologically distinct from changes that
occur due to cell death via necrosis (Fig.
21.30). In necrosis cells typically burst and
release their contents outside. This damages
surrounding cells and can lead to inflammation.
In apoptosis, cells shrink, condense, and
fragment without the release of cell contents.
Cell fragments known as apoptotic bodies are
later phagocytosed. Three types of proteins
control cell death. Killer proteins initiate
apoptosis, destruction proteins digest DNA and
other cellular components, and engulfment
proteins are required in phagocytosis.
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Overview of Apoptosis Pathways
Apoptosis pathways discovered by genetic studies
in worms and mammals are shown in Fig. 21.33.
Proteins such as the CED-9 and Bcl-2 homologs
serve as sensors of signals that regulate
apoptosis. In the presence of a trophic factor,
these regulators block the activation of adaptor
proteins (CED-4 and Apaf-1) and thereby prevent
effector proteins (the CED-3, Casp9, and Casp3
proteases) from becoming activated. These
effectors are enzymes known as caspases. When
activated, caspases cause cells to undergo
apoptosis by cleaving key intracellular
substrates resulting in a cascade of events
leading to disassembly of cellular structures and
death.
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Apoptosis in Motor Neuron Development
In the development of the nervous system, motor
neurons and other neurons must establish
connections between themselves and tissues they
innervate, such as muscle. Typically, more
neurons grow initially and migrate towards the
target tissue than ultimately will survive. Those
that fail to form connections to the target
tissue are selected for apoptosis. Grafting
studies performed with embryos showed that the
formation of connections and survival of
developing neurons depends on the quantity of
neurotrophic factors they receive from the target
field tissue they will innervate (Fig. 21.35).
The greater the quantity of factors received, the
higher the percentage of cell survival.
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Neurotrophins and Their Receptors
Neurotrophic factors (neurotrophins) include
nerve growth factor (NGF), neurotrophin-3 (NT-3),
and brain-derived neurotrophic factor (BDNF). The
receptors for neurotrophins are RTKs named Trks.
Trk receptors reside on the cell surface of
neurons and bind to their ligands released from
the tissues that they will eventually innervate.
Studies with knockout mice have established some
of the roles of neurotrophins in nervous system
development (Fig. 21.36). When the genes encoding
NGF or its receptor TrkA are knocked out, mice
selectively fail to form nociceptive
(pain-sensing) neurons that innervate the skin.
Knockout of the genes encoding NT-3 or its
receptor TrkC inhibits the formation of
propioceptive neurons that innervate skeletal
muscle fibers. These studies show that
neurotrophin signaling is required for developing
neurons to survive instead of undergoing
apoptosis.
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Caspase Activation in the Absence of Trophic
Factors
The mechanism by which caspases are activated in
the absence of a trophic factor (e.g., NGF) is
illustrated in Fig. 21.38. In the absence of the
trophic factor, the pro-apoptotic protein Bad
inhibits the anti-apoptotic protein Bcl-2. As a
result, Bcl-2 cannot inhibit the activity of the
Bax pro-apoptotic protein. This results in
release of cytochrome c (Cyt c) from
mitochondria. Cyt c binds to the Apaf-1 adaptor
protein, and this triggers procaspase 9 to
undergo activation. Caspase 9 then
cleaves and activates procaspase 3. Caspase 3
cleaves substrates leading to alterations that
result in cell death. Caspase activation and cell
death can also be triggered by binding of death
signals, such as tumor necrosis factor (TNF?) to
cells (not shown).
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Inhibition of Caspase Activation by Trophic
Factors
In the presence of a trophic factor, caspases are
maintained in their inactive pro-forms (Fig.
21.38). In neurons, NGF causes Bad to be
phosphorylated and inactivated via the PI-3
kinase/PKB signaling pathway. Under these
conditions Bcl-2 can inhibit the activity of Bax.
This prevents Cyt c release from mitochondria and
blocks the activation of procaspase 9 by Apaf-1.