Gene knockouts

The tissue-specific patterns of expression of the PPAR. isotypes suggested that these proteins have distinct physiological roles, and this was further supported when each was specifically disrupted in mouse gene knockout models. 

Subtype Name Comments Result of Gene Knockout in Mice ... 

Gene knockouts were performed by homologous recombination in mice. The enzymes are characterized as neuronal, inducible (macrophage), and endothelial because these were the sites in which they were first identified. However, all three enzymes have been found in other sites, and the neuronal enzyme is also inducible. Each gene has been cloned, and its chromosomal location in humans has been determined. 

The stability of phytoene desaturase and lycopene cyclase transcripts also influenced accumulation of carotenoids. Efforts in directed evolution of carotenogenic enzymes have also continued. Alternate approaches using systematic and combinatorial gene knockout targets have allowed for enhancement of carotenoid production in the absence of a priori assumptions of regulatory mechanisms. 

Alper, H., Miyaoku, K., and Stephanopoulos, G., Construction of lycopene-overproducing E. coli strains by combining systematic and combinatorial gene knockout targets, Nat. Biotechnol. 23, 612, 2005... 

Ohtsu, H. Watanabe, T. (2003). New functions of histamine found in histidine decarboxylase gene knockout mice. Biochem. Biophys. Res. Commun. 305, 443-7. 

Eguchi, N., et at (2002). Sleep in transgenic and gene-knockout mice for... 

Orexin receptor type 1 gene knockout (OXiR-/-)... 

Orexin receptor type 2 gene knockout (OX2K / )... 

Reeves, A.R., Britain, I.A., Cemota, W.H. et al. (2006) Effects of methylmalonyl-CoA mutase gene knockouts on erythromycin production in carbohydrate-based and oil-based fermentations of Saccharopolyspora ery-thraea. Journal of Industrial Microbiology and Biotechnology, 33, 600-609. 

The first gene-knockout mouse to become available was a mouse lacking detectable P-gp in the brain capillary endothelial cells. This has been used to elegantly... 

Biosynthesis of polyamines is essential for growth and multiplication of T. brucei, hence discovery of drug candidates that inhibit enzymes in the polyamine biosynthesis pathway represent an attractive approach to development of trypanocides. The consequences of gene knockout of ornithine decarboxylase (ODC), the target of eflornithine (3), have been further characterized and suggest that new inhibitors of this enzyme may be particularly effective [18]. 

Inhibition of cytokine activity in vivo by administration of monoclonal antibodies (and, more recently, by gene knockout studies) continues to elucidate the physiological and pathophysiological effect of various cytokines. 

The importance of P0 in PNS myelin has been clearly demonstrated. In P0 gene knockout experiments in mice [40], severe hypomyelination and a virtual absence of compact myelin in the PNS is observed. In humans, there are two disease states associated with mutations in the P0 gene Charcot-Marie-Tooth type I disease (see Ch. 38) and Dejerine-Sottas disease, both dysmyelinating diseases that exhibit a spectrum of severity depending on the particular mutation. 

While the conditional gene knockout experiments are supportive of a role for the NMDA receptors in memory, they are less than fully conclusive in linking the synaptic coincidence-detection feature of the NMDA receptor to memory formation. Like all loss-of-function studies, CA1-specific gene-knockout experiments could, in theory, produce memory impairment via a mechanism independent of the coincidence-detection function of the NMDA receptor. For example, one may argue that the physical absence of the NMDA receptor channels may cause subtle structural reconfiguration at the synapse, thereby altering normal synaptic transmission. Therefore, the memory impairment in CA1-specific NR1 knockout mice does not allow a firm conclusion that the coincidence-detection function of NMDA receptors controls learning and memory processes at the cellular level. 

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