Recent advances in mammalian genomics are providing unprecedented opportunities to identify genes that influence neural systems relevant to psychiatric illnesses. As a genetically tractable mammalian species in which complex behaviors may be modeled, mice have been the focus of much attention for examining relationships between genes and behavior. Many investigators are pursuing experimental strategies in which the functions of known genes are examined by studying the impact of their manipulation in mice. These studies are providing important information regarding genetic influences on behavior, as well as animal models relevant to human disease processes. Additional powerful genetic strategies have recently been initiated to search broadly for genes that influence particular clinically relevant behavioral traits. These approaches promise to uncover a large number of novel genetic influences on neuronal pathways that regulate behavior. In this review, mouse molecular genetic techniques are described and illustrative examples of their application to neurobehavioral processes relevant to clinical disorders are provided. Future directions in technology development that promise to further enhance the utility of these approaches for translational research are also described.
Schematic representations of transgenic and gene targeting procedures. A, To generate transgenic mice, fertilized eggs are collected and a transgenic DNA construct is microinjected into a pronucleus. The construct commonly contains a gene of interest linked to promoter sequences designed to direct gene expression to cell types of interest. The injected eggs are surgically transferred into the oviducts of surrogate mothers. Transmission of the transgene to the offspring is commonly determined by Southern blot analysis of DNA. B, To generate mice with targeted mutations, DNA targeting constructs are introduced into embryonic stem (ES) cells, which are subsequently screened for gene targeting events. Targeted ES cells are microinjected into mouse embryos, which are subsequently surgically transferred into the uteri of surrogate mothers. Chimeric mice containing a mixture of cells derived from the host embryo and the injected ES cells are bred with wild-type mice. Germ line transmission of the mutation is assessed in the offspring.
Schematic representations of quantitative trait loci analysis and N-ethyl-N-nitrosourea (ENU) mutagenesis. A, Representative chromosomes are shown from 2 inbred strains, F1 hybrids, and F2 generations that have differing polymorphisms at chromosomal locations A, B, and C. These polymorphisms can be detected by gel electrophoresis. The mice of the F2 generation are tested on a behavioral task, and the distribution of their behavioral scores is examined. A genome scan of the DNA from high and low responders is performed, and the possible association of the BB/CC and bb/cc genotypes is illustrated to localize a quantitative trait locus (QTL). B, A scheme for detection of dominant mutations. ENU mutagenesis is performed by treating male mice with ENU and then breeding them to the G1 generation. G1 mice undergo behavioral testing for a phenotype of interest. Extreme responders are examined to confirm an association between an induced mutation and the behavioral phenotype.
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