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The Journal of Neuroscience, February 1, 1998, 18(3):1009-1019

Bcl-x_L is an Antiapoptotic Regulator for Postnatal CNS Neurons

Alexander Sh. Parsadanian¹, Yu Cheng¹, Cynthia R. Keller-Peck¹, David M. Holtzman^{1, 2}, and William D. Snider¹

¹ Center for the Study of Nervous System Injury, Department of Neurology and ² Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110

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 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-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.

Key words: apoptosis; axotomy; hypoxia-ischemia; Bcl-x_L; Ced 9; Bax

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Copyright © 1998 Society for Neuroscience  0270-6474/98/1831009-11$05.00/0

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