Loss of apoptosis-inducing factor results in cell-type-specific neurogenesis defects.

Authors

R Ishimura
G R. Martin
S L. AckermanFollow

Document Type

Article

Publication Date

2008

Keywords

Apoptosis, Apoptosis-Inducing-Factor, Cell-Cycle, Cerebellum, Embryonic-Development, G1-Phase, Gene-Deletion, Mesencephalon, Mice-Mutant-Strains, Neurons, Purkinje-Cells, S-Phase, Stem-Cells, Time-Factors

First Page

4938

Last Page

4948

JAX Source

J Neurosci 2008 May; 28(19):4938-48.

Abstract

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.

Recommended Citation

Ishimura R, Martin GR, Ackerman SL. Loss of apoptosis-inducing factor results in cell-type-specific neurogenesis defects. J Neurosci 2008 May; 28(19):4938-48.