Biotechnology

Production of knockout rats using ENU mutagenesis and a yeast-based screening assay. Zan, Y. et al. Nature Biotechnol. 21, 645–651 (2003)

The rat is often the preferred model in many areas of biomedical research, but its use has been hampered by the inability to produce gene-disrupted knockout rats. This challenge has now been overcome by Zan et al., who have developed a protocol that combines rat germline mutagenesis using ENU with yeast-based assays that screen for functional mutations in selected genes, which they demonstrate by generating rat knockouts for the breast-cancer suppressor genes Brca1 and Brca2.

Neurodegenerative Disease

GSK-3α regulates production of Alzheimer's disease amyloid-β peptides. Phiel, C. J. et al. Nature 423, 435–439 (2003)

Alzheimer's disease is associated with increased production and aggregation of amyloid-β (Aβ) peptides, which are produced by proteolytic processing of the amyloid precursor protein (APP). The authors show that glycogen synthase kinase-3α (GSK-3α) facilitates APP processing, and that lithium blocks the production of Aβ peptides by inhibiting GSK-3α. Lithium, which is used to treat bipolar disorder, has a narrow therapeutic window and a higher frequency of side effects in older patients, but agents that specifically target GSK-3α might prove to be valuable in the treatment of Alzheimer's disease.

Cardiopulmonary Disease

Heterozygous deficiency of hypoxia-inducible factor-2α protects mice against pulmonary hypertension and right ventricular dysfunction during prolonged hypoxia. Brusselmans, K. et al. J. Clin. Invest. 111, 1519–1527 (2003)

Present therapies for pulmonary hypertension — a common complication of chronic obstructive pulmonary disease that often leads to right ventricular hypertrophy and heart failure — have limited success. Brusselmans et al. provide evidence that the transcription factor hypoxia-inducible factor-2α (HIF-2α) is important in the pathogenesis of pulmonary hypertension, indicating that inhibition of HIF-2α could be a promising strategy for this disease.

Biotechnology

Expression profiling reveals off-target gene regulation by RNAi. Jackson, A. L. et al. Nature Biotechnol. 21, 635–637 (2003)

RNA inteference using small interfering RNAs (siRNAs) designed to match specific messenger RNA sequences has been generating considerable excitement as a potent method to suppress gene expression, with its apparent high specificity being a particularly attractive characteristic. However, by using large-scale gene expression profiling, Jackson et al. have shown that siRNAs can cross-react with targets of limited sequence similarity, suggesting that this possibility should be carefully considered when designing and interpreting siRNA-based experiments.