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The Journal of Neuroscience, December 8, 2004, 24(49):11205-11213; doi:10.1523/JNEUROSCI.1436-04.2004

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Development/Plasticity/Repair
Programmed Cell Death of Adult-Generated Hippocampal Neurons Is Mediated by the Proapoptotic Gene Bax

Woong Sun,^1,2 Adam Winseck,¹ Sharon Vinsant,¹ Ok-hee Park,² Hyun Kim,² and Ronald W. Oppenheim¹

¹Department of Neurobiology and Anatomy and Neuroscience Program, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, and ²Department of Anatomy, Brain Korea 21, Korea University College of Medicine, Sungbuk-Gu, Seoul, Korea 136-705

In the dentate gyrus (DG) of the adult mouse hippocampus, a substantial number of new cells are generated daily, but only a subset of these survive and differentiate into mature neurons, whereas the majority undergo programmed cell death (PCD). However, neither the intracellular machinery required for adult stem cell-derived neuronal death nor the biological implications of the significant loss of these newly generated cells have been examined. Several markers for apoptosis failed to reveal cell death in Bax-deficient mice, and this, together with a progressive increase in neuron number in the DG of the Bax knock-out, indicates that Bax is critical for the PCD of adult-generated hippocampal neurons. Whereas the proliferation of neural progenitor cells was not altered in the Bax-knock-out, there was an accumulation of doublecortin, calretinin⁺, and neuronal-specific nuclear protein⁺ postmitotic neurons, suggesting that Bax-mediated PCD of adult-generated neurons takes place during an early phase of differentiation. The absence of PCD in the adult also influenced the migration and maturation of adult-generated DG neurons. These results suggest that PCD in the adult brain plays a significant role in the regulation of multiple aspects of adult neurogenesis.

Key words: adult neurogenesis; Bax; cell death; mouse; proliferation; migration; differentiation

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Received Nov 28, 2003; revised November 1, 2004; accepted November 1, 2004.

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