Hirschsprung disease (HSCR) is a leading cause of intestinal dysmotility resulting from a reduced enteric nervous system (ENS) and leading to lack of distal intestine innervations. HSCR can be caused by mutations in several different loci and shows considerable phenotypic variation: individuals carrying the same allele can differ in the extent of intestinal denervation and severity of enterocolitis, intestinal inflammation of unknown etiology that is a serious HSCR complication. The sources of these phenotypic variations in HSCR are not well understood. If we could identify factors that make some individuals healthier than others, we would gain insight into potential therapies for those with more serious disease. We have a panel of zebrafish ENS mutants that serve as models for understanding variation in HSCR. Zebrafish is an excellent model in which to study HSCR phenotypic variation because we can manipulate all of the relevant parameters. Our zebrafish mutants have different extents of distal intestine denervation, often with considerable phenotypic variation among mutants that share the same genotype. These mutants also exhibit variation in intestinal motility, variation in their intestinal bacterial communities, and variation in intestinal inflammation. We propose that alterations in the ENS phenotype in ENS mutants, including changes in specific neuronal subtypes, result in dysmotility that causes changes in the milieu of the intestinal lumen. This, in turn, can lead to formation of altered bacterial communities that can cause inflammation by recruiting neutrophils, cells of the innate immune system that respond to bacteria and are a hallmark of intestinal inflammation. We also propose that changes in the intestinal bacterial community composition and in inflammation can feed back to the ENS to amplify variation in intestinal motility. We will test these hypotheses by manipulating the ENS phenotype, intestinal bacterial composition, and neutrophil influx and comparing all of these processes in individual animals of known genotypes. We will follow bacterial colonization, neutrophil recruitment, and intestinal motility in living animals in real time. Our proposed studies will provide new information about how the ENS regulates the composition of the intestinal bacterial community and inflammation, and how these processes feed back onto the ENS to amplify intestinal pathology. This information will provide new insights into the mechanisms of phenotypic variation in HSCR, expand our understanding of phenotypic variation in human disease, and may reveal new targets for therapies.

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Hirschsprung disease is a prevalent cause of intestinal dysmotility, affecting 1:5000 live births, and is often accompanied by debilitating intestinal enterocolitis of unknown origin. The proposed studies use zebrafish models to uncover the origins of variation in Hirschsprung-associated intestinal pathology and enterocolitis, paving the way toward better clinical diagnoses and treatments.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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University of Oregon
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Ferreira, Carlos R; Xia, Zhi-Jie; Clément, Aurélie et al. (2018) A Recurrent De Novo Heterozygous COG4 Substitution Leads to Saul-Wilson Syndrome, Disrupted Vesicular Trafficking, and Altered Proteoglycan Glycosylation. Am J Hum Genet 103:553-567
Logan, Savannah L; Dudley, Christopher; Baker, Ryan P et al. (2018) Automated high-throughput light-sheet fluorescence microscopy of larval zebrafish. PLoS One 13:e0198705
Clément, Aurélie; Blanco-Sánchez, Bernardo; Peirce, Judy L et al. (2018) Cog4 is required for protrusion and extension of the epithelium in the developing semicircular canals. Mech Dev :
Parthasarathy, Raghuveer (2018) Monitoring microbial communities using light sheet fluorescence microscopy. Curr Opin Microbiol 43:31-37
Troll, Joshua V; Hamilton, M Kristina; Abel, Melissa L et al. (2018) Microbiota promote secretory cell determination in the intestinal epithelium by modulating host Notch signaling. Development 145:
Dona, Margo; Slijkerman, Ralph; Lerner, Kimberly et al. (2018) Usherin defects lead to early-onset retinal dysfunction in zebrafish. Exp Eye Res 173:148-159
Blanco-Sánchez, Bernardo; Clément, Aurélie; Fierro Jr, Javier et al. (2018) Grxcr1 Promotes Hair Bundle Development by Destabilizing the Physical Interaction between Harmonin and Sans Usher Syndrome Proteins. Cell Rep 25:1281-1291.e4
Rolig, Annah S; Sweeney, Emily Goers; Kaye, Lila E et al. (2018) A bacterial immunomodulatory protein with lipocalin-like domains facilitates host-bacteria mutualism in larval zebrafish. Elife 7:
Logan, Savannah L; Thomas, Jacob; Yan, Jinyuan et al. (2018) The Vibrio cholerae type VI secretion system can modulate host intestinal mechanics to displace gut bacterial symbionts. Proc Natl Acad Sci U S A 115:E3779-E3787
Ganz, J; Baker, R P; Hamilton, M K et al. (2018) Image velocimetry and spectral analysis enable quantitative characterization of larval zebrafish gut motility. Neurogastroenterol Motil 30:e13351

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