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Axonal Lesion-Induced Dpysl3 mRNA Expression in Immature Neurons is Unaffected by Myelin-Specific T Cells

ABSTRACT: Knowing the effect of autoimmune CNS-targeting T cells on the expression of neurogenesis-associated genes is essential to understand their putative effect on hippocampal functioning. Here, we used RNA microarray analysis to study the effect of myelin-specific T cells on the gene profile in the dentate gyrus 2 days after a perforant pathway transection, when neural precursor cells are highly proliferating. By the use of Gene Ontology analysis, the MANGO database and the Allan Mouse Brain Atlas, we identified dihydropyrimidinase-like 3 (Dpysl3), due to its expression in the subgranular zone of the dentate gyrus. In situ hybridizations and quantification of Dpysl3 mRNA+ grains in the subgranular zone and granular cell layer showed a significant increase in Dpysl3 mRNA in axonal lesioned compared to control mice, and no effect of the myelin-specific T cells. Dpysl3 mRNA was not expressed in Ki-67 mRNA+ proliferating cells and NeuN mRNA+ mature neurons, but it was expressed in Nestin mRNA+ neural precursor cells and even more so in Dcx mRNA+ migrating neuroblasts. These results suggest that the regulation of Dpysl3 mRNA expression in immature granular neurons is refractory to inflammatory mediators secreted by the myelin-specific T cells, while being highly responsive to neuronal stimuli. Comparable mechanisms may support normal hippocampal functioning in diseases characterized by infiltration of autoimmune CNS-targeting T cells, such as multiple sclerosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE78044 | GEO | 2017/02/01

SECONDARY ACCESSION(S): PRJNA312407

REPOSITORIES: GEO

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Project description:We sought to find molecular signatures of the SGZ cell types, and to characterize the molecular pathways and transcription factor cascades that define the neurogenic niche. We used laser capture microdissection and DNA microarrays to profile gene expression in the inner (SGZ) and outer portions of the dentate gyrus (DG). Since the vast majority of the cells in the DG are mature granule cells, we compared the expression of the inner and outer portions to reveal molecular markers for the less numerous populations of the SGZ. This data set is part of a larger study assessing conserved molecular signatures of neurogenesis in the hippocampal subgranular zone of rodents and primates. Using a combination of selective SGZ transcriptional profiling with laser microdissection and DNA microarrays as well as in situ hybridization (ISH), we developed an extensive molecular characterization of the mouse SGZ, identifying 367 genes enriched in the SGZ compared to mature granule neurons. These genes displayed a wide range of cellular expression patterns reflecting the cellular milieu of the SGZ, including progenitor and dividing cells, immature granule cells, astrocytes, oligodendrocytes, and GABAergic interneurons. We next used a comparable microarray data set in rhesus monkey that profiled the SGZ across postnatal development to identify genes related to developmentally regulated granule cell neurogenesis. The rhesus monkey SGZ showed highly significant similarity to mouse, whereas network analysis of these data identified SGZ-enriched gene sets with different temporal profiles reflecting differential time-courses for maturation of glia and granule neurons. One neurogenesis-related gene network showed a steady decrease in expression across postnatal rhesus development from birth to adulthood. This temporal pattern is highly correlated with the number of proliferating cells in the dentate gyrus, and the neurogenic transcription factors Sox4 and Sox11 are central hub genes for this gene network. A number of the genes in this network showed a similar postnatal downregulation in mouse, suggesting a general conservation of molecular mechanisms underlying developmental and adult neurogenesis in rodents and primates. Primate data available at: http://www.blueprintnhpatlas.org/ Brains from 10- to 11-week-old C57BL/6 male mice housed in three conditions (no running, 4 days of running, 30 days of running) were sectioned and the dentate gyrus was isolated. For each brain, the inner granule cell layer (containing the subgranular zone) and outer GCL were separated using laser capture microdissection, and RNA from each region was collected and processed as described in the protocols.

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Axonal Lesion-Induced Dpysl3 mRNA Expression in Immature Neurons is Unaffected by Myelin-Specific T Cells

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