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Mutations in genes encoding general transcription factors cause neurological disorders. Despite clinical prominence, the consequences of defects in the basal transcription machinery during brain development are unclear. We found that loss of the TATA-box binding protein-associated factor TAF8, a component of the general transcription factor TFIID, in the developing central nervous system affected the expression of many, but notably not all genes. Taf8 deletion caused apoptosis, unexpectedly restricted to forebrain regions. Nuclear levels of the transcription factor p53 were elevated in the absence of TAF8, as were the mRNAs of the pro-apoptotic p53 target genes Noxa, Puma and Bax. The cell death in Taf8 forebrain regions was completely rescued by additional loss of p53, but Taf8 and p53 brains failed to initiate a neuronal expression program. Taf8 deletion caused aberrant transcription of promoter regions and splicing anomalies. We propose that TAF8 supports the directionality of transcription and co-transcriptional splicing, and that failure of these processes causes p53-induced apoptosis of neuronal cells in the developing mouse embryo. [Image: see text]

The majority of emerging infectious diseases have their source in animals, and emergence occurs at the human/animal interface, when infections in animals breech the species barrier to infect humans, the population in which they are often first identified. The response is frequently characterized by a series of emergency activities to contain and manage the infection in human populations, and at the same time to identify the source of the infection in nature. If infection is found to have a source in animals, and if animals cause a continuous threat of human infection, culling is often recommended with severe economic impact. Currently, efforts are being undertaken for closer interaction at the animal/human interface through joint surveillance and risk assessment between the animal and human medicine sectors, and research is underway in geographic areas where emergence at the animal/human interface has occurred in the past. The goal of this research is to identify infectious organisms in tropical and other wild animals, to genetically sequence these organisms, and to attempt to predict which organisms have the potential to emerge in human populations. It may be more cost-effective to learn from past emergence events, and to shift the paradigm from disease surveillance, detection, and response in humans; to prevention of emergence at the source by understanding and mitigating the factors, or determinants, that influence animal infection. These determinants are clearly understood from the study of previous emergence events and include human-induced changes in natural environments, urban areas, and agricultural systems; raising and processing animal-based foods; and the roles of global trade, migration, and climate change. Better understanding of these factors learned from epidemiological investigation of past and present emergence events, and modeling and study of the cost-effectiveness of interventions that could result in their mitigation, could provide evidence necessary to better address the political and economic barriers to prevention of infections in animals. Such economically convincing arguments for change and mitigation are required because of the basic difference in animal health—driven by the need for profit; and human health—driven by the need to save lives.