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Cell type specific gene expression : profiling and targeting

  • Author(s): Nathanson, Jason Lawrence
  • et al.
Abstract

The mammalian central nervous system is a complex network of functionally and anatomically intertwined cell-types. The roles of particular cell types in brain function and development are determined by precise patterns of connectivity, synaptic function and intrinsic integration of external signals, and are best understood when the cell type is isolated and directly studied. We were particularly interested in cell types contributing to the neurogenic niche of the subgranular zone (SGZ) of the hippocampus. The SGZ is an extremely diverse environment containing many different cell types, including mature granule cells, inhibitory interneurons, astrocytes, oligodendrocytes, endothelial cells, stem cells, dividing cells and immature neurons. We used laser capture microdissection, DNA microarrays and anatomical-based expression clustering to identify SGZ enriched genes expressed in the diverse cell types of this region. Over- representation of gene ontology terms suggested cell type specific functional roles including inter and extra- cellular signal transduction, cell division, and cell differentiation. Further exploration of cell type roles can be achieved by specifically manipulating cell types using viruses. We found that adeno-associated virus serotype 1 (AAV1) preferentially transduced inhibitory neurons, and thus may be useful for studying this cell type. However, we sought further restriction to subtypes of inhibitory neurons. Towards this goal, we focused on creating inhibitory neurons subtype specific promoters for use in viruses. We tested short regulatory sequences derived from Takifugu Rubripes (fugu), human, mouse, and composite regulatory elements. We found that all fugu promoters drove expression in mammalian inhibitory neurons, but none drove expression in a cell type specific manner. Mammalian-derived and composite regulatory element promoters also showed only limited abilities to restrict expression to inhibitory neuron subtypes. These results suggest a complex regulatory environment distinguishes expression in inhibitory neuron subtypes. Future efforts to target subtypes of inhibitory neurons or other cell types may utilize the topographical and functional links shared between genes identified in the SGZ microarray screen

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