A Cell Cycle-Based Mechanism of Apoptosis
The E2F–Cdc2 Cell-Cycle Pathway Specifically Mediates Activity Deprivation-Induced Apoptosis of Postmitotic Neurons
Yoshiyuki Konishi and Azad Bonni (see pages1649-1658)
Recent studies suggest that cell-cycle proteins are involved not only in the generation of neurons but also in their death. In this issue, Konishi and Bonni make use of one of the best-studied cellular models of neuronal apoptosis, cerebellar granule cells, to examine the role of the protein kinase Cdc2, a cyclic-dependent kinase, in cell death. Precursors of granule cells in the superficial (external granule) layer of the cerebellum differentiate and then migrate to their final position in the internal granule cell layer. Some postmitotic granule cells undergo apoptosis during this early period of development. Granule cell apoptosis can be triggered in vitro by withdrawal of growth factors or by reduced neuronal activity. In fact, granule cells have long been cultured under depolarizing conditions (high external potassium), because depolarization promotes their survival. Previous studies by these authors indicated that activity deprivation activates Cdc2, leading to phosphorylation of the Bcl-2-associated protein (BAD), and apoptosis. They now report that transcriptional activation of Cdc2 involves the binding of the transcription factor E2F1. Overexpression of E2F1 in granule cells induced Cdc2 and increased apoptosis. Interestingly, activity deprivation did not induce the E2F1-sensitive genes involved in DNA synthesis and replication in proliferating cells. Furthermore, growth factor withdrawal did not induce Cdc2. Thus Cdc2 appears to be a specific target of E2F1 in the signal pathway leading to apoptosis induced by activity deprivation in postmitotic neurons.
LIF and Self-Renewal in the Olfactory Epithelium
Leukemia Inhibitory Factor Is a Key Signal for Injury-Induced Neurogenesis in the Adult Mouse Olfactory Epithelium
S. Bauer, S. Rasika, Jing Han, C. Mauduit, M. Raccurt, G. Morel, F. Jourdan, M. Benahmed, E. Moyse, and P. H. Patterson (see pages 1792-1803)
The olfactory epithelium represents a unique structure for studies of neurogenesis because olfactory sensory neurons (OSNs) are constantly renewed throughout life. This process can be experimentally manipulated by removal of the olfactory bulb, the target for olfactory sensory axons. Bulbectomy triggers widespread death of the target-deprived OSNs, followed several days later by an increase in newly generated OSNs. In this issue, Bauer et al. made use of this system to examine the mechanisms responsible for self-renewal. They report the specific induction of the cytokine leukemia inhibitory factor (LIF) within hours after olfactory bulb ablation. LIF can be induced in glia after neural injury, but in this case, the dying OSNs appeared to be the major source of the mitogen. Overexpression of LIF or its absence in knock-out mice suggested that LIF is required for the enhanced neurogenesis. Thus the cells destined to die produce a factor necessary for the proliferation of a new generation of OSNs. The authors suggest that release of a self-renewing mitogenic signal could occur in other apoptotic cells, and may have implications for the mechanisms of neuronal repair in other brain regions.
Imaging Cerebellar LTD In Vivo
Optical Imaging of Long-Term Depression in the Mouse Cerebellar Cortex In Vivo
Wangcai Gao, Robert L. Dunbar, Gang Chen, Kenneth C. Reinert, John Oberdick, and Timothy J. Ebner (see pages 1859-1866)
Long-term depression (LTD) in the cerebellum is a robust in vitro model of synaptic plasticity. In LTD, the conjunctive activation of parallel fibers (pfs) and climbing fibers (cfs) leads to sustained depression of the parallel fiber synapse between granule cells and Purkinje cells. In vitro studies have provided us with a good understanding of the cellular and molecular basis for LTD. In addition, the anatomy of these pathways suggests that LTD should show highly specific spatial expression, because pfs are transversely oriented while cfs are parasagittally oriented. In this issue, Gao et al. use in vivo imaging to provide a striking picture of this spatial specificity. They used optical imaging with neutral red, a pH-sensitive dye, to monitor neuronal activity in anesthetized mice. Conjunctive stimulation of both pathways was followed by a prolonged reduction in the optical signal where the beam of activity induced by pf stimulation crossed the parasagittal bands of activity induced by stimulation of climbing fibers.