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The Journal of Neuroscience, July 5, 2006, 26(27):7257-7264; doi:10.1523/JNEUROSCI.0196-06.2006

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Neurobiology of Disease
BH3-Only Proapoptotic Bcl-2 Family Members Noxa and Puma Mediate Neural Precursor Cell Death

Rizwan S. Akhtar,^1,2 Ying Geng,¹ Barbara J. Klocke,¹ Cecelia B. Latham,¹ Andreas Villunger,³ Ewa M. Michalak,⁴ Andreas Strasser,⁴ Steven L. Carroll,¹ and Kevin A. Roth^1,2

¹Division of Neuropathology, Department of Pathology and ²Department of Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama 35294, ³Division of Experimental Pathophysiology and Immunology, Biocenter, Innsbruck Medical University, A-6020 Innsbruck, Austria, and ⁴The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia

Correspondence should be addressed to Dr. Kevin A. Roth, Division of Neuropathology, Department of Pathology, University of Alabama at Birmingham, Sparks Center 961, 1530 3rd Avenue South, Birmingham, AL 35294-0017. Email: kroth{at}path.uab.edu

Neural precursor cells (NPCs) are highly sensitive to genotoxic injury, which triggers activation of the intrinsic mitochondria-dependent apoptotic pathway. This pathway is typically initiated by members of the BH3 (Bcl-2 homology 3)-only subgroup of the Bcl-2 (B-cell CLL/lymphoma 2) protein family, which are positioned upstream in the apoptotic pathway to respond to specific death stimuli. We have shown previously that NPCs deficient in the tumor suppressor protein p53 show significantly less death after exposure to genotoxic injury or to staurosporine (STS), a broad kinase inhibitor and potent apoptosis inducer. p53 has been shown to regulate the expression of both Noxa and Puma, two BH3-only proteins, although their involvement in p53-dependent cell death appears to be cell-type and stimulus specific. A systematic comparison of the relative contributions of Noxa and Puma to NPC apoptosis has not yet been performed. We hypothesized that p53-dependent transcription of Noxa and Puma leads to death in telencephalic NPCs exposed to genotoxic stress. We found that genotoxic injury induces a rapid p53-dependent increase in expression of Noxa and Puma mRNA in telencephalic NPCs. Furthermore, deficiency of either Noxa or Puma inhibited DNA damage-induced caspase-3 activation and cell death in telencephalic NPCs in vitro. However, only Puma deficiency protected telencephalic ventricular zone NPCs from death in vivo. In contrast to genotoxic injury, STS produced a p53-independent increase in Noxa and Puma expression, but neither Noxa nor Puma was required for STS-induced NPC death. Together, these experiments identify Noxa and Puma as important regulators of genotoxin-induced telencephalic NPC death.

Key words: caspases; apoptosis; Bcl-2; p53; transcription; staurosporine

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Received Jan. 16, 2006; revised May 24, 2006; accepted May 28, 2006.

Correspondence should be addressed to Dr. Kevin A. Roth, Division of Neuropathology, Department of Pathology, University of Alabama at Birmingham, Sparks Center 961, 1530 3rd Avenue South, Birmingham, AL 35294-0017. Email: kroth{at}path.uab.edu

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