2Ј,5Ј-Oligoadenylate-dependent RNase L functions in the interferon-inducible, RNA decay pathway known as the 2-5A system. To determine the physiological roles of the 2-5A system, mice were generated with a targeted disruption of the RNase L gene. The antiviral effect of interferon α was impaired in RNase L -/-mice providing the first evidence that the 2-5A system functions as an antiviral pathway in animals. In addition, remarkably enlarged thymuses in the RNase L -/-mice resulted from a suppression of apoptosis. There was a 2-fold decrease in apoptosis in vivo in the thymuses and spleens of RNase L -/-mice. Furthermore, apoptosis was substantially suppressed in RNase L -/-thymocytes and fibroblasts treated with different apoptotic agents. These results suggest that both interferon action and apoptosis can be controlled at the level of RNA stability by RNase L. Another implication is that the 2-5A system is likely to contribute to the antiviral activity of interferon by inducing apoptosis of infected cells.

The phylogenetically conserved nuclear factor I (NFI) family of transcription/replication proteins is essential both for adenoviral DNA replication and for the transcription of many cellular genes. We showed previously that the four murine NFI genes ( Nfia , Nfib , Nfic, and Nfix ) are expressed in unique but overlapping patterns during mouse development and in adult tissues. Here we show that disruption of the Nfia gene causes perinatal lethality, with >95% of homozygous Nfia −/− animals dying within 2 weeks after birth. Newborn Nfia −/− animals lack a corpus callosum and show ventricular dilation indicating early hydrocephalus. Rare surviving homozygous Nfia −/− mice lack a corpus callosum, show severe communicating hydrocephalus, a full-axial tremor indicative of neurological defects, male-sterility, low female fertility, but near normal life spans. These findings indicate that while the Nfia gene appears nonessential for cell viability and DNA replication in embryonic stem cells and fibroblasts, loss of Nfia function causes severe developmental defects. This finding of an NFI gene required for a developmental process suggests that the four NFI genes may have distinct roles in vertebrate development.

N-CoR (nuclear hormone receptor corepressor) was identified originally as a corepressor that binds to, and mediates transcriptional repression by, nuclear hormone receptors (Hö rlein et al. 1995). Thyroid-hormone and retinoic-acid receptors (TR and RAR) of the nuclear hormone receptor family actively repress the transcription of target genes in the absence of ligand (Chambon 1994;Mangelsdorf et al. 1995). Transcriptional repression is mediated by a conserved region in the aminoterminal part of the ligand-binding domain of TR (Baniahmad et al. 1995). N-CoR binds to the ligand-binding domain, termed the Co-R box, and, thereby, mediates transcriptional repression (Hö rlein et al. 1995). N-CoR is a large protein with a molecular mass of 270,000 (Mr 270K), and contains three repressor domains in its amino-terminal region (Hö rlein et al. 1995). Another corepressor, SMRT, which also binds to the Co-R box, shows striking homology to N-CoR (Chen and Evans 1995). N-CoR also forms a complex with mammalian Sin3 orthologs (mSin3A and mSin3B), which bind to another repressor, Mad (Alland et al. 1997;Hassing et al. 1997;Heinzel et al. 1997;Laherty et al. 1997;Nagy et al. 1997). The basic helix-loop-helix (bHLH) proteins of the Mad family act as transcriptional repressors after heterodimerization with Max (Ayer et al. 1993). N-CoR is required for Mad-induced transcriptional repression. The same target sequence of Mad/Max, the so-called E-box, is also recognized by a heterodimer of Myc/Max that activates transcription. It is believed that transcriptional activation of a group of target genes by Myc/Max enhances cellular proliferation or transformation, whereas transcriptional repression of the same target genes by Mad/Max leads to suppression of proliferation or induction of terminal differentiation in a wide range of cell types Chin et al. 1995;Roussel et al. 1996)

During organogenesis, neural and mesenchymal progenitor cells give rise to many cell lineages, but their molecular requirements for self-renewal and lineage decisions are incompletely understood. In this study, we show that their survival critically relies on the redundantly acting SoxC transcription factors Sox4, Sox11 and Sox12. The more SoxC alleles that are deleted in mouse embryos, the more severe and widespread organ hypoplasia is. SoxC triple-null embryos die at midgestation unturned and tiny, with normal patterning and lineage specification, but with massively dying neural and mesenchymal progenitor cells. Specific inactivation of SoxC genes in neural and mesenchymal cells leads to selective apoptosis of these cells, suggesting SoxC cell-autonomous roles. Tead2 functionally interacts with SoxC genes in embryonic development, and is a direct target of SoxC proteins. SoxC genes therefore ensure neural and mesenchymal progenitor cell survival, and function in part by activating this transcriptional mediator of the Hippo signalling pathway.

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