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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Blanco-Sánchez, Bernardo; Clément, Aurélie; Fierro Jr, Javier et al. (2014) Complexes of Usher proteins preassemble at the endoplasmic reticulum and are required for trafficking and ER homeostasis. Dis Model Mech 7:547-59
McMenamin, Sarah K; Bain, Emily J; McCann, Anna E et al. (2014) Thyroid hormone-dependent adult pigment cell lineage and pattern in zebrafish. Science 345:1358-61
Santos, M Emília; Braasch, Ingo; Boileau, Nicolas et al. (2014) The evolution of cichlid fish egg-spots is linked with a cis-regulatory change. Nat Commun 5:5149
Beahm, Brendan J; Dehnert, Karen W; Derr, Nicolas L et al. (2014) A visualizable chain-terminating inhibitor of glycosaminoglycan biosynthesis in developing zebrafish. Angew Chem Int Ed Engl 53:3347-52
DeLaurier, April; Huycke, Tyler R; Nichols, James T et al. (2014) Role of mef2ca in developmental buffering of the zebrafish larval hyoid dermal skeleton. Dev Biol 385:189-99
Kimmel, Charles B (2014) Skull developmental modularity: a view from a single bone - or two. J Appl Ichthyol 30:600-607
Beck, Bodo B; Phillips, Jennifer B; Bartram, Malte P et al. (2014) Mutation of POC1B in a severe syndromic retinal ciliopathy. Hum Mutat 35:1153-62
Sheehan-Rooney, Kelly; Swartz, Mary E; Zhao, Feng et al. (2013) Ahsa1 and Hsp90 activity confers more severe craniofacial phenotypes in a zebrafish model of hypoparathyroidism, sensorineural deafness and renal dysplasia (HDR). Dis Model Mech 6:1285-91
Paquette, Colleen E; Kent, Michael L; Buchner, Cari et al. (2013) A retrospective study of the prevalence and classification of intestinal neoplasia in zebrafish (Danio rerio). Zebrafish 10:228-36
Rodriguez-Mari, Adriana; Canestro, Cristian; BreMiller, Ruth A et al. (2013) Retinoic acid metabolic genes, meiosis, and gonadal sex differentiation in zebrafish. PLoS One 8:e73951

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