Development of the CNS follows a pattern of neuronal precursor cell proliferation localized within specific germinal zones giving rise to cells that exit the cell cycle, differentiate, and migrate to their proper positions in the brain. Classically, differentiated neurons have been characterized as postmitotic, and while the nature of neuronal cell cycle exit is still poorly understood, it appears to be permanent; cell cycle proteins are downregulated and postmitotic neurons lose the ability to reenter the cell cycle (27,28). The fact that cancers of adult neuron origin are extremely rare, or even unknown, is strongly supportive of this permanency. The small amount of neurogenesis that takes place in the adult brain is restricted to a pool of neural stem cells thought to be the remnants of the ventricular and subventricular zones (29). Contrary to this, however, is more recent evidence that neurons do indeed retain the capacity to reenter the cell cycle, but instead of leading to proliferation, engagement of the cell cycle machinery leads to apoptosis.
Early indications that cell cycle reentry of postmitotic neurons leads to apoptosis came from the creation of transgenic mice in which the oncogenic SV40 T-antigen was expressed in Purkinje cells using the Purkinje cell-specific pcp2 gene promoter (7). Rather than increasing Purkinje cell proliferation, transgenic mice were ataxic, owing to disrupted cerebellar cortical development and progressive Purkinje cell degeneration. The expression of the SV40 T-antigen, which binds and inactivates the cell cycle-controlling retinoblas-toma protein (pRb), induced what appeared to be an initial cell cycle attempt, including DNA synthesis as measured by bromodeoxyuridine (BrdU) incorporation, but rather than dividing, the Purkinje cells died. In a similar study at the same time, the SV40 T-antigen was expressed in the retina of transgenic mice using a rhodopsin promoter. Like Purkinje cells, the expression of SV40 T-antigen in the retina resulted in neuronal death; in this case, photoreceptor degeneration and blindness (5). The knockout of pRb entirely in mice by three different laboratories further suggested that permanent exit from the cell cycle is absolutely required for neuronal survival. Retinoblastoma-deficient mice died during embryogenesis and had profound defects in neurogenesis. Having failed to differentiate, neurons exiting the ventricular zone appeared to continue proliferating and subsequently died (6,8,9). Together, these findings led to the suggestion that cell cycle processes may be intimately connected to the death of terminally differentiated neurons, such that progression through the cell cycle after cell cycle reentry is aborted resulting in a mitotic catastrophe and apoptosis (30).
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