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The Journal of Neuroscience, May 7, 2008, 28(19):4938-4948; doi:10.1523/JNEUROSCI.0229-08.2008

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Neurobiology of Disease
Loss of Apoptosis-Inducing Factor Results in Cell-Type-Specific Neurogenesis Defects

Ryuta Ishimura,¹ Gail R. Martin,² and Susan L. Ackerman¹

¹Howard Hughes Medical Institute and The Jackson Laboratory, Bar Harbor, Maine 04609, and ²Department of Anatomy, University of California, San Francisco, San Francisco, California 94158-2324

Correspondence should be addressed to Dr. Susan L. Ackerman, The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609. Email: susan.ackerman{at}jax.org

Mitochondrial dysfunction is commonly associated with neurodegeneration in the aging brain. In addition, the importance of mitochondrial function during brain development is illustrated by the neurological deficits observed in infants with mitochondrial complex deficiencies. However, the extent to which abnormalities in mitochondrial function might impact neurogenesis during brain development is not well understood. Previously, we demonstrated that adult harlequin (Hq) mutant mice, which have an 80% reduction in the mitochondrial protein apoptosis-inducing factor (AIF), exhibited signs of oxidative stress and progressive loss of adult cerebellar and retinal neurons. To assess whether in addition to its role in postmitotic neuron survival Aif is also necessary for cerebellar development, we analyzed embryos in which Aif was deleted in the prospective midbrain and cerebellum at a very early stage of development using an En1 (engrailed 1) promoter-driven cre recombinase gene. These mutant mice, which died at birth, had midbrain defects and dramatic deficits in cerebellar Purkinje and granule cell precursors. Additional analysis revealed that Aif-null Purkinje cell precursors prematurely entered S-phase, but most failed to undergo mitosis and ultimately died via apoptosis. In contrast, proliferation of mutant granule cell precursors was blocked before S-phase. Mice in which Aif was deleted later in embryogenesis using a nestin promoter-driven cre gene survive for several days after birth, and postnatal granule cell precursors in these mice also failed to enter S-phase. Our results indicate that the loss of Aif results in cell cycle abnormalities in a neuron-specific manner during cerebellar development.

Key words: conditional knock-out; Purkinje cell precursor; cell cycle arrest; G1-phase; granule cell precursor; S-phase; apoptosis; cerebellum

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Received Aug. 8, 2007; revised March 12, 2008; accepted March 31, 2008.

Correspondence should be addressed to Dr. Susan L. Ackerman, The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609. Email: susan.ackerman{at}jax.org

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