Glucocorticoid receptor (GR) activation induces apoptosis of granule cells in the hippocampus. In contrast, neuroprotection is seen after mineralocorticoid receptor (MR) activation. To date there is no in vivo evidence for direct interactions between corticosteroids and any of the key regulatory molecules of programmed cell death. In this report, we show that the opposing actions of MR and GR on neuronal survival result from their ability to differentially influence the expression of members of the bcl-2 gene family; specifically, in the rat hippocampus, activation of GR induces cell death by increasing the ratio of the proapoptotic molecule Bax relative to the antiapoptotic molecules Bcl-2 or Bcl-x(L); the opposite effect is observed after stimulation of MR. The same results were obtained in both young and aged animals; however, older subjects (which were more susceptible to GR-mediated apoptosis) tended to express the antiapoptotic genes more robustly. Using a loss-of-function mouse model, we corroborated the observations made in the rat, demonstrating Bax to be essential in the GR-mediated cell death-signaling cascade. In addition, we show that GR activation increases and MR activation decreases levels of the tumor suppressor protein p53 (a direct transcriptional regulator of bax and bcl-2 genes), thus providing new information on the early genetic events linking corticosteroid receptors with apoptosis in the nervous system.

Bcl-2 is a major regulator of programmed cell death, a critical process in shaping the developing nervous system. To assess whether Bcl-2 is involved in regulating neuronal survival and in mediating the neuroprotective action of neurotrophic factors, we generated Bcl-2-deficient mice. At birth, the number of facial motoneurons, sensory, and sympathetic neurons was not significantly changed, and axotomy-induced degeneration of facial motoneurons could still be prevented by brain-derived neurotrophic factor (BDNF) or ciliary neurotrophic factor (CNTF). Interestingly, substantial degeneration of motoneurons, sensory, and sympathetic neurons occurred after the physiological cell death period. Accordingly, Bcl-2 is not a permissive factor for the action of neurotrophic factors, and although it does not influence prenatal neuronal survival, it is crucial for the maintenance of specific populations of neurons during the early postnatal period.

We have used a reconstituted cell-free transcription system to investigate the molecular basis of mitotic repression of RNA polymerase I (pol I) transcription. We demonstrate that SL1, the TBP-containing promoter-binding factor, is inactivated by cdc2/cyclin B-directed phosphorylation, and reactivated by dephosphorylation. Transcriptional inactivation in vitro is accompanied by phosphorylation of two subunits, e.g. TBP and hTAF I 110. To distinguish whether transcriptional repression is due to phosphorylation of TBP, hTAF I 110 or both, SL1 was purified from two HeLa cell lines that express either full-length or the core domain of TBP only. Both TBP-TAF I complexes exhibit similar activity and both are repressed at mitosis, indicating that the variable N-terminal domain which contains multiple target sites for cdc2/cyclin B phosphorylation is dispensable for mitotic repression. Protein-protein interaction studies reveal that mitotic phosphorylation impairs the interaction of SL1 with UBF. The results suggest that phosphorylation of SL1 is used as a molecular switch to prevent pre-initiation complex formation and to shut down rDNA transcription at mitosis.

Neural stem cells (NSCs) generate new hippocampal dentate granule neurons throughout adulthood. The genetic programs controlling neuronal differentiation of adult NSCs are only poorly understood. Here we show that, in the adult mouse hippocampus, expression of the SoxC transcription factors Sox4 and Sox11 is initiated around the time of neuronal commitment of adult NSCs and is maintained in immature neurons. Overexpression of Sox4 and Sox11 strongly promotes in vitro neurogenesis from adult NSCs, whereas ablation of Sox4/Sox11 prevents in vitro and in vivo neurogenesis from adult NSCs. Moreover, we demonstrate that SoxC transcription factors target the promoters of genes that are induced on neuronal differentiation of adult NSCs. Finally, we show that reprogramming of astroglia into neurons is dependent on the presence of SoxC factors. These data identify SoxC proteins as essential contributors to the genetic network controlling neuronal differentiation in adult neurogenesis and neuronal reprogramming of somatic cells.