Bcl-x(L) is a death-inhibiting member of the Bcl-2/Ced9 family of proteins which either promote or inhibit apoptosis. Gene targeting has revealed that Bcl-X(L) is required for neuronal survival during brain development; however, Bcl-X(L) knock-out mice do not survive past embryonic day 13.5, precluding an analysis of Bcl-x(L) function at later stages of development. Bcl-X(L) expression is maintained at a high level postnatally in the CNS, suggesting that it may also regulate neuron survival in the postnatal period. To explore functions of Bcl-x(L) related to neuron survival in postnatal life, we generated transgenic mice overexpressing human Bcl- x(L) under the control of a panneuronal promoter. A line that showed strong overexpression in brainstem and a line that showed overexpression in hippocampus and cortex were chosen for analysis. We asked whether overexpression of Bcl-x(L) influences neuronal survival in the postnatal period by studying two injury paradigms that result in massive neuronal apoptosis. In the standard neonatal facial axotomy paradigm, Bcl-x(L) overexpression had substantial effects, with survival of 65% of the motor neurons 7 d after axotomy, as opposed to only 15% in nontransgenic littermates. To investigate whether Bcl-x(L) regulates survival of CNS neurons in the forebrain, we used a hypoxia-ischemia paradigm in neonatal mice. We show here that hypoxia-ischemia leads to substantial apoptosis in the hippocampus and cortex of wild-type neonatal mice. Furthermore, we show that overexpression of Bcl-x(L) is neuroprotective in this paradigm. We conclude that levels of Bcl-X(L) in postnatal neurons may be a critical determinant of their susceptibility to apoptosis.
|Number of pages||11|
|Journal||Journal of Neuroscience|
|State||Published - 1998|
- Ced 9