Essential role for survivin in early brain development.
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.
Jiang
Yuying
Y
Center for Childhood Cancer, Columbus Children's Research Institute, Columbus, Ohio 43205, USA.
de Bruin
Alain
A
Caldas
Hugo
H
Fangusaro
Jason
J
Hayes
John
J
Conway
Edward M
EM
Robinson
Michael L
ML
Altura
Rachel A
RA
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001921:Brain / Q000166:cytology / Q000196:embryology* / Q000502:physiology; D005260:Female; D017353:Gene Deletion; D051034:Inhibitor of Apoptosis Proteins; D019426:Integrases / Q000235:genetics; D007381:Intermediate Filament Proteins / Q000235:genetics; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics; D064231:Nestin; D009474:Neurons / Q000166:cytology* / Q000502:physiology; D010641:Phenotype; D011247:Pregnancy; D012097:Repressor Proteins; D012160:Retina / Q000166:cytology / Q000196:embryology* / Q000502:physiology; D000077022:Survivin
C117749:Birc5 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D007381:Intermediate Filament Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D012097:Repressor Proteins; D000077022:Survivin; C045073:Cre recombinase; D019426:Integrases