Bcl-xLis an Antiapoptotic Regulator for Postnatal CNS Neurons

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Abstract
Bcl-xLis a death-inhibiting member of the Bcl-2/Ced9 family of proteins which either promote or inhibit apoptosis. Gene targeting has revealed that Bcl-xLis required for neuronal survival during brain development; however,Bcl-xLknock-out mice do not survive past embryonic day 13.5, precluding an analysis of Bcl-xLfunction at later stages of development. Bcl-xLexpression 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-xLrelated to neuron survival in postnatal life, we generated transgenic mice overexpressing humanBcl-xLunder the control of a pan-neuronal 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-xLinfluences 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-xLoverexpression 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-xLregulates 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-xLis neuroprotective in this paradigm. We conclude that levels of Bcl-xLin postnatal neurons may be a critical determinant of their susceptibility to apoptosis.