The mammalian central nervous system (CNS) is composed of a complex network of numerous distinct neuron types that are functionally and anatomically intertwined. The function of the circuits in which these neurons are embedded is dependent on the precise and cell type specific regulation of connectivity, synaptic function, and intrinsic integration of external signals. Thus, in order to conduct experiments to better understand the basic mechanisms of nervous system function or to develop and implement treatments for neurological dysfunction, it is highly desirable to have tools that can specifically target neuron types. Genetic methods therefore hold great promise for the study and therapeutic manipulation of CNS circuits because it is possible to harness the same mechanisms that regulate differential gene expression in neurons to drive the specific expression of transgenes. There are numerous transgenes which are being used or developed to allow studies or manipulation of neural circuits at the level of specificity of individual cell types. This genetic arsenal is likely to continue to grow in both size and sophistication within the next several years. The utility of all of these genetic methods, however, hinges on the ability to specifically drive gene expression in cell types of interest. This proposal aims to identify short promoter sequences from the genome of Fugu rubripes (""""""""Fugu"""""""") which can be used to selectively drive gene expression in specific types of mammalian cortical neurons. The identification of such promoter sequences is expected to provide crucial tools for the study of cortical circuits. Short promoter sequences can be used not only in the generation of transgenic mice, but also can be used along with small capacity viruses for the control of gene expression in other species, or for the generation of non-murine transgenic animals or transgenic """"""""knockdown"""""""" animals using lentivirus. Small capacity viruses are also among the most promising vectors presently available for human gene therapy in the brain, and their eventual use for this purpose will also require effective short promoters.
| Nathanson, J L; Yanagawa, Y; Obata, K et al. (2009) Preferential labeling of inhibitory and excitatory cortical neurons by endogenous tropism of adeno-associated virus and lentivirus vectors. Neuroscience 161:441-50 |
| Nathanson, Jason L; Jappelli, Roberto; Scheeff, Eric D et al. (2009) Short Promoters in Viral Vectors Drive Selective Expression in Mammalian Inhibitory Neurons, but do not Restrict Activity to Specific Inhibitory Cell-Types. Front Neural Circuits 3:19 |
