Loss of apoptosis-inducing factor results in cell-type-specific neurogenesis defects.
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.
Ishimura
Ryuta
R
Howard Hughes Medical Institute and The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
Martin
Gail R
GR
Ackerman
Susan L
SL
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051033:Apoptosis Inducing Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D002453:Cell Cycle / Q000502:physiology; D002531:Cerebellum / Q000196:embryology*; D047108:Embryonic Development / Q000502:physiology; D016193:G1 Phase / Q000502:physiology; D017353:Gene Deletion; D008636:Mesencephalon / Q000196:embryology; D051379:Mice; D008817:Mice, Mutant Strains; D009474:Neurons / Q000502:physiology; D011689:Purkinje Cells / Q000166:cytology; D016196:S Phase / Q000502:physiology; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D013997:Time Factors
D051033:Apoptosis Inducing Factor