| http://purl.uniprot.org/citations/30364784 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/30364784 | http://www.w3.org/2000/01/rdf-schema#comment | "Background & aimsMicrovillus inclusion disease (MVID) is a congenital intestinal malabsorption disorder caused by defective apical vesicular transport. Existing cellular models do not fully recapitulate this heterogeneous pathology. The aim of this study was to characterize 3-dimensional intestinal organoids that continuously generate polarized absorptive cells as an accessible and relevant model to investigate MVID.MethodsIntestinal organoids from Munc18-2/Stxbp2-null mice that are deficient for apical vesicular transport were subjected to enterocyte-specific differentiation protocols. Lentiviral rescue experiments were performed using human MUNC18-2 variants. Apical trafficking and microvillus formation were characterized by confocal and transmission electron microscopy. Spinning disc time-lapse microscopy was used to document the lifecycle of microvillus inclusions.ResultsLoss of Munc18-2/Stxbp2 recapitulated the pathologic features observed in patients with MUNC18-2 deficiency. The defects were fully restored by transgenic wild-type human MUNC18-2 protein, but not the patient variant (P477L). Importantly, we discovered that the MVID phenotype was correlated with the degree of enterocyte differentiation: secretory vesicles accumulated already in crypt progenitors, while differentiated enterocytes showed an apical tubulovesicular network and enlarged lysosomes. Upon prolonged enterocyte differentiation, cytoplasmic F-actin-positive foci were observed that further progressed into classic microvillus inclusions. Time-lapse microscopy showed their dynamic formation by intracellular maturation or invagination of the apical or basolateral plasma membrane.ConclusionsWe show that prolonged enterocyte-specific differentiation is required to recapitulate the entire spectrum of MVID. Primary organoids can provide a powerful model for this heterogeneous pathology. Formation of microvillus inclusions from multiple membrane sources showed an unexpected dynamic of the enterocyte brush border."xsd:string |
| http://purl.uniprot.org/citations/30364784 | http://purl.org/dc/terms/identifier | "doi:10.1016/j.jcmgh.2018.08.001"xsd:string |
| http://purl.uniprot.org/citations/30364784 | http://purl.uniprot.org/core/author | "Michaux G."xsd:string |
| http://purl.uniprot.org/citations/30364784 | http://purl.uniprot.org/core/author | "de Saint Basile G."xsd:string |
| http://purl.uniprot.org/citations/30364784 | http://purl.uniprot.org/core/author | "Sepulveda F.E."xsd:string |
| http://purl.uniprot.org/citations/30364784 | http://purl.uniprot.org/core/author | "Farin H.F."xsd:string |
| http://purl.uniprot.org/citations/30364784 | http://purl.uniprot.org/core/author | "Maschalidi S."xsd:string |
| http://purl.uniprot.org/citations/30364784 | http://purl.uniprot.org/core/author | "Bidaud-Meynard A."xsd:string |
| http://purl.uniprot.org/citations/30364784 | http://purl.uniprot.org/core/author | "Nicolle O."xsd:string |
| http://purl.uniprot.org/citations/30364784 | http://purl.uniprot.org/core/author | "Mosa M.H."xsd:string |
| http://purl.uniprot.org/citations/30364784 | http://purl.uniprot.org/core/author | "Menche C."xsd:string |
| http://purl.uniprot.org/citations/30364784 | http://purl.uniprot.org/core/author | "Michels B.E."xsd:string |
| http://purl.uniprot.org/citations/30364784 | http://purl.uniprot.org/core/date | "2018"xsd:gYear |
| http://purl.uniprot.org/citations/30364784 | http://purl.uniprot.org/core/name | "Cell Mol Gastroenterol Hepatol"xsd:string |
| http://purl.uniprot.org/citations/30364784 | http://purl.uniprot.org/core/pages | "477-493.e1"xsd:string |
| http://purl.uniprot.org/citations/30364784 | http://purl.uniprot.org/core/title | "Dynamic Formation of Microvillus Inclusions During Enterocyte Differentiation in Munc18-2-Deficient Intestinal Organoids."xsd:string |
| http://purl.uniprot.org/citations/30364784 | http://purl.uniprot.org/core/volume | "6"xsd:string |
| http://purl.uniprot.org/citations/30364784 | http://www.w3.org/2004/02/skos/core#exactMatch | http://purl.uniprot.org/pubmed/30364784 |
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| http://purl.uniprot.org/uniprot/#_B4DY46-mappedCitation-30364784 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/30364784 |