title: Sox10 haploinsufficiency affects maintenance of progenitor cells in a mouse model of Hirschsprung disease.
abstract: Hirschsprung disease, or congenital megacolon, is characterized by aganglionosis of the terminal bowel, which leads to intestinal obstruction and chronic constipation. Several genes involved in the disease have been identified. In particular, haploinsufficiency of SOX10, which encodes a transcription factor, results in megacolon, often in combination with other disorders. Although Hirschsprung disease has been recognized as a neurocristopathy, the cellular mechanisms that lead to aganglionosis in affected individuals are unclear. Failure of mutant enteric progenitor cells to migrate into the gut, to survive, or to differentiate into appropriate cell types at the appropriate time and in correct numbers might contribute to the disease phenotype. In the present study, we use mice with a targeted deletion of Sox10 to study the etiology of Hirschsprung disease. We demonstrate that neural crest-derived enteric progenitors that are heterozygous for the Sox10 mutation colonize the proximal intestine and are unaffected in their survival capacity. However, unlike their wild-type counterparts, mutant enteric neural crest-derived cells are unable to maintain their progenitor state and acquire preneuronal traits, which results in a reduction of the progenitor pool size. Thus, the cells that normally colonize the hindgut are depleted in the Sox10 mutant, causing the distal bowel to become aganglionic.
authors.affiliation: Institute of Cell Biology, Department of Biology, Swiss Federal Institute of Technology, ETH-Hönggerberg, CH-8093 Zurich, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Paratore
authors.forename: Christof
authors.initials: C
authors.lastname: Eichenberger
authors.forename: Ueli
authors.initials: U
authors.lastname: Suter
authors.forename: Lukas
authors.initials: L
authors.lastname: Sommer
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005724:Ganglia / Q000378:metabolism / Q000473:pathology; D006579:Heterozygote; D006609:High Mobility Group Proteins / Q000235:genetics* / Q000378:metabolism; D006627:Hirschsprung Disease / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009154:Mutation; D055757:SOXE Transcription Factors; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors
chemical_list: D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D055757:SOXE Transcription Factors; C527924:Sox10 protein, mouse; D014157:Transcription Factors