| Summary: | Nerve injury causes death of motor nerve cells (motoneurons) in neonatal mammals, in
sharp contrast to motoneurons in adult mammals, which survive and regenerate their severed
processes (axons). Injured neonatal motoneurons die by an active form of cell death, called
apoptosis, whereby the cell activates its own proteases to rapidly breakdown the cell. Both death
promoting and survival promoting genes orchestrate the activation of this form of cell death.
Motoneurons in neonatal mice with a null mutation in the pro-death gene Bax are able to survive
nerve injury. Similarly overexpression of either the survival promoting gene, Bcl-2 or Bcl-xL
also protects neonatal motoneurons from nerve injury-induced cell death suggesting that the level
of expression of cell death and survival genes plays a role in the susceptibility of motoneurons to
injury-induced apoptosis. The susceptibility of young motoneurons to nerve injury has also been
attributed to a dependence on trophic factors supplied by the target muscle. In support of this
theory, application of trophic factors to the injured nerve stump rescues neonatal motoneurons
from apoptosis. In this thesis, I have examined the expression and activation of survival and
death-promoting genes and their role in the apoptotic death pathway. The three main findings
are presented here.
Firstly, the endogenous expression of death promoting genes, Bax and Caspase-3 is
higher and the expression of anti-apoptotic Bcl-2 is lower in neonatal motoneurons in
comparison with adult motoneurons. The relative ratio of Bcl-2:Bax expression increases -10-
fold during postnatal development, which may contribute to the increased survival of adult
motoneurons after axotomy.
Secondly, activation o f the cell death pathway requires mitochondrial involvement. The
release of death-inducing factors from the mitochondria is required for the activation o f caspases,
the proteases which rapidly breakdown the cell. The Bax-mediated pathway and an
excitotoxic/calcium-mediated pathway converge at the mitochondria to induce the release of proapoptotic
factors that activate caspases and breakdown the cell.
Thirdly, application of trophic factors, BDNF or GDNF, rescues neonatal motoneurons
from apoptosis by preventing loss of the survival-signaling pathway (maintaining high levels of
Akt phosphorylation) and preventing activation of the mitochondrial death pathway.
This thesis provides support for the concept that neonatal motoneuron survival is
dependent on target-derived trophic factors and provides insights into the injury-induced
apoptotic pathway and the importance of trophic factor signaling as a repressor of cell death. === Science, Faculty of === Zoology, Department of === Graduate
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