BCL-X(L) IS AN ANTIAPOPTOTIC REGULATOR FOR POSTNATAL CNS NEURONS

Bcl-x(L) is a death-inhibiting member of the Bcl-2/Ced9 family of prot eins which either promote or inhibit apoptosis. Gene targeting has rev ealed that Bcl-x(L) is required for neuronal survival during brain dev elopment; however, Bcl-x(L) knock-out mice do not survive past embryon ic day 13.5, precluding an analysis of Bcl-x(L) function at later stag es of development. Bcl-x(L) expression is maintained at a high level p ostnatally in the CNS, suggesting that it may also regulate neuron sur vival in the postnatal period. To explore functions of Bcl-x(L) relate d to neuron survival in postnatal life, we generated transgenic mice o verexpressing human Bcl-x(L) under the control of a pan-neuronal promo ter. A line that showed strong overexpression in brainstem and a line that showed overexpression in hippocampus and cortex were chosen for a nalysis. We asked whether overexpression of Bcl-x(L) influences neuron al survival in the postnatal period by studying two injury paradigms t hat result in massive neuronal apoptosis. In the standard neonatal fac ial axotomy paradigm, Bcl-x(L) overexpression had substantial effects, with survival of 65% of the motor neurons 7 d after axotomy, as oppos ed to only 15% in nontransgenic littermates. To investigate whether Bc l-x(L) regulates survival of CNS neurons in the forebrain, we used a h ypoxia-ischemia paradigm in neonatal mice. We show here that hypoxia-i schemia leads to substantial apoptosis in the hippocampus and cortex o f wildtype 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 thei r susceptibility to apoptosis.