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The Journal of Neuroscience, June 11, 2008, 28(24):6068-6078; doi:10.1523/JNEUROSCI.4940-07.2008

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Neurobiology of Disease
Mcl-1 Is a Key Regulator of Apoptosis during CNS Development and after DNA Damage

Nicole Arbour,^1,3 * Jacqueline L. Vanderluit,^2,3 * J. Nicole Le Grand,^2,3 Arezu Jahani-Asl,^2,3 Vladimir A. Ruzhynsky,^2,3 Eric C. C. Cheung,^2,3 Melissa A. Kelly,^2,3 Alexander E. MacKenzie,⁴ David S. Park,^2,3 Joseph T. Opferman,⁵ and Ruth S. Slack^2,3

¹Department of Biochemistry, Microbiology, and Immunology, ²Department of Cellular and Molecular Medicine, and ³Neuroscience Program, Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5, ⁴Children's Hospital of Eastern Ontario Apoptosis Research Center, Ottawa, Ontario, Canada K1H 8L1, and ⁵St. Jude Children's Research Hospital, Memphis, Tennessee 39105-2794

Correspondence should be addressed to Dr. Ruth S. Slack, Neuroscience Research Group, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5. Email: rslack{at}uottawa.ca

Despite the importance of Mcl-1, an anti-apoptotic Bcl-2 family member, in the regulation of apoptosis, little is known regarding its role in nervous system development and injury-induced neuronal cell death. Because germline deletion of Mcl-1 results in peri-implantation lethality, we address the function of Mcl-1 in the nervous system using two different conditional Mcl-1 mouse mutants in the developing nervous system. Here, we show for the first time that Mcl-1 is required for neuronal development. Neural precursors within the ventricular zone and newly committed neurons in the cortical plate express high levels of Mcl-1 throughout cortical neurogenesis. Loss of Mcl-1 in neuronal progenitors results in widespread apoptosis. Double labeling with active caspase 3 and Tuj1 reveals that newly committed Mcl1 deficient neurons undergo apoptosis as they commence migration away from the ventricular zone. Examination of neural progenitor differentiation in vitro demonstrated that cell death in the absence of Mcl1 is cell autonomous. Although conditional deletion of Mcl-1 in cultured neurons does not trigger apoptosis, loss of Mcl-1 sensitizes neurons to an acute DNA damaging insult. Indeed, the rapid reduction of Mcl-1 mRNA and protein levels are early events after DNA damage in neurons, and maintaining high Mcl-1 levels can protect neurons against death. Together, our results are the first to demonstrate the requirement of Mcl-1, an anti-apoptotic Bcl-2 family protein, for cortical neurogenesis and the survival of neurons after DNA damage.

Key words: neurogenesis; cell death; neuronal progenitors; neuron; apoptosis; development

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Received Nov. 1, 2007; revised March 26, 2008; accepted April 30, 2008.

Correspondence should be addressed to Dr. Ruth S. Slack, Neuroscience Research Group, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5. Email: rslack{at}uottawa.ca

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