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The Journal of Neuroscience, July 27, 2005, 25(30):6962-6970; doi:10.1523/JNEUROSCI.1446-05.2005

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Development/Plasticity/Repair
Essential Role for Survivin in Early Brain Development

Yuying Jiang,¹ Alain de Bruin,³ Hugo Caldas,¹ Jason Fangusaro,^1,4 John Hayes,² Edward M. Conway,⁵ Michael L. Robinson,^1,4 and Rachel A. Altura^1,4

¹Center for Childhood Cancer and ²Center for Injury Research and Policy, Columbus Children's Research Institute, Columbus, Ohio 43205, ³Human Cancer Genetics Program, Department of Molecular Virology, Immunology, and Medical Genetics, and ⁴Department of Pediatrics, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio 43210, and ⁵Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, University of Leuven, B-3000 Leuven, Belgium

Apoptosis is an essential process during normal neuronal development. Approximately one-half of the neurons produced during neurogenesis die before completion of CNS maturation. To characterize the role of the inhibitor of apoptosis gene, survivin, during neurogenesis, we used the Cre-loxP-system to generate mice lacking survivin in neuronal precursor cells. Conditional deletion of survivin starting at embryonic day 10.5 leads to massive apoptosis of neuronal precursor cells in the CNS. Conditional mutants were born at the expected Mendelian ratios; however, these died shortly after birth from respiratory insufficiency, without primary cardiopulmonary pathology. Newborn conditional mutants showed a marked reduction in the size of the brain associated with severe, mutifocal apoptosis in the cerebrum, cerebellum, brainstem, spinal cord, and retina. Caspase-3 and caspase-9 activities in the mutant brains were significantly elevated, whereas bax expression was unchanged from controls. These results show that survivin is critically required for the survival of developing CNS neurons, and may impact on our understanding of neural repair, neural development, and neurodegenerative diseases. Our study is the first to solidify a role for survivin as an antiapoptotic protein during normal neuronal development in vivo.

Key words: survivin; brain development; retina; neuron; embryo; gene deletion; apoptosis; mice

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Received Jan 5, 2005; revised June 17, 2005; accepted June 18, 2005.

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