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By Emily Cartwright, PhD
When it's late in the afternoon and you smell a delicious bag of popcorn in the microwave, your mouth begins to water and your stomach starts to grumble. These behaviors are a result of communication between your enteric nervous system (ENS) and brain. The ENS is an arm of the peripheral nervous system and is critically important for function of the gastrointestinal (GI) tract, controlling everything from salivation to excretion. Dysfunction of the ENS leads to significant problems, from mild diarrhea to severe bowel obstructions and inflammatory bowel disease (IBD). Autism spectrum disorder (ASD) and Parkinson’s disease (PD) are two neurological disorders with potential ENS involvement, as both are associated with gut dysmotility early in the disease course. Increasing our understanding of ENS involvement in these intestinal and extraintestinal diseases could improve early detection and inform future treatments.
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In a recent study by Drokhlyansky et al., researchers examined the expression of various risk genes associated with intestinal (IBD, Hirschsprung (HSCR)) and extraintestinal diseases (ASD and PD) within different cell subsets of the mucosa (epithelial cells, immune cells, neurons, and glia). A g is usually identified through a genome-wide association study (GWAS) comparing individuals with and without a disease. The study found that risk genes associated with IBD are mostly expressed by epithelial cells and immune cells, while the expression of other genes, like gastrin releasing peptide (GRP), is primarily within ENS neurons.These results suggest that the pathogenesis of IBD is complex, with interactions between epithelial cells, immune cells, and the ENS all likely contributing to disease. In contrast to IBD, 4 of the 5 the risk genes examined for HSCR are highly expressed in the ENS, including RET, the gene most associated with HSCR1. Most risk genes examined for ASD and PD were also identified in ENS neurons, though the cellular expression pattern was diverse.
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(Left) Immunohistochemical staining of immersion fixed paraffin-embedded sections of human spinal cord with Goat Anti-Ret Polyclonal Antibody (AF1485) at 3 µg/mL followed by incubation with VisUCyte™ HRP Polymer Antibody (VC004). Tissue was stained using DAB (brown) and counterstained with hematoxylin (blue). Specific staining was localized to motor neurons. (Right) Western Blot showing tissue extracts from mouse and rat brain probed with Gastrin-releasing Peptide R/GRPR Antibody [NBP1-30937]. HRP-conjugated anti-rabbit IgG Secondary Antibody was used to detect the GRPR. |
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To elucidate the relative contribution of the ENS to intestinal and extraintestinal diseases, the researchers analyzed risk gene expression in ENS compared to neurons in the CNS. Increased expression of a risk gene within the ENS suggests that this system may be more affected by a loss of function mutation. Many risk genes for HSCR and IBD were enriched in the ENS compared to CNS, emphasizing the importance of the ENS in these intestinal diseases. Strikingly, several risk genes for ASD and PD were enriched in the ENS compared to CNS, including DSCAM, ANK2, and DLG2/PSD93. This is surprising, as ASD and PD are traditionally considered neurological diseases and current diagnosis relies on behavioral, not GI, symptoms. Increased expression of risk genes in the ENS compared to CNS suggests a greater role of the ENS in disease etiology and merits further investigation. These data have important implications for understanding disease pathogenesis, as well as diagnosis, of ASD and PD.
Immunocytochemical staining of A172 human glioblastoma cell line with Goat Anti-DSCAM Polyclonal Antibody (AF3666). Cells were stained with the NorthernLights™ 557-conjugated Secondary Antibody (NL001) (red) and counterstained with DAPI (blue).
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Emily Cartwright, Postdoctoral Research Associate
University of Minnesota
Emily studies how costimulatory signaling domain selection impacts phenotype and function of cellular immunotherapies for chronic viral infections.
Research in focus
Drokhlyansky, E., Smillie, C. S., Van Wittenberghe, N., Ericsson, M., Griffin, G. K., Eraslan, G., Dionne, D., Cuoco, M. S., Goder-Reiser, M. N., Sharova, T., Kuksenko, O., Aguirre, A. J., Boland, G. M., Graham, D., Rozenblatt-Rosen, O., Xavier, R. J., & Regev, A. (2020). The Human and Mouse Enteric Nervous System at Single-Cell Resolution. Cell. https://doi.org/10.1016/j.cell.2020.08.003
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