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Review
. 2024 Jul 1;223(7):e202310118.
doi: 10.1083/jcb.202310118. Epub 2024 Apr 29.

Modeling the cell biology of monogenetic intestinal epithelial disorders

Izumi Kaji  1   2   3 , Jay R Thiagarajah  4   5   6 , James R Goldenring  1   2   3   7
Affiliations
Review

Modeling the cell biology of monogenetic intestinal epithelial disorders

Izumi Kaji et al. J Cell Biol. .

Abstract

Monogenetic variants are responsible for a range of congenital human diseases. Variants in genes that are important for intestinal epithelial function cause a group of disorders characterized by severe diarrhea and loss of nutrient absorption called congenital diarrheas and enteropathies (CODEs). CODE-causing genes include nutrient transporters, enzymes, structural proteins, and vesicular trafficking proteins in intestinal epithelial cells. Several severe CODE disorders result from the loss-of-function in key regulators of polarized endocytic trafficking such as the motor protein, Myosin VB (MYO5B), as well as STX3, STXBP2, and UNC45A. Investigations of the cell biology and pathophysiology following loss-of-function in these genes have led to an increased understanding of both homeostatic and pathological vesicular trafficking in intestinal epithelial cells. Modeling different CODEs through investigation of changes in patient tissues, coupled with the development of animal models and patient-derived enteroids, has provided critical insights into the enterocyte differentiation and function. Linking basic knowledge of cell biology with the phenotype of specific patient variants is a key step in developing effective treatments for rare monogenetic diseases. This knowledge can also be applied more broadly to our understanding of common epithelial disorders.

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Conflict of interest statement

Disclosures: The authors declare no competing interests exist.

Figures

Figure 1.
Figure 1.
Intestinal brush border structure and function. (A) Intestinal epithelium consists of a variety of cell types lining the luminal surface along the crypt-villus axis of mucosal architecture. PAS staining of tissues visualizes glycoproteins as dark purple and represents a good histological marker for mature brush border and goblet cells. Individual microvillus structure is demonstrated by scanning electron microscopy (SEM). (B) Absorptive transporters for nutrients and water in the microvillus. After protein synthesis, the apical membrane transporters are trafficked by post-Golgi vesicles and inserted into the membrane. Apical membranes containing some transporters can be endocytosed and either recycled or fused with lysosomes to facilitate degradation. This figure was created with Biorender.
Figure 2.
Figure 2.
A pathway for investigation of the cellular physiology of CODE disorders exemplified by investigations of microvillus inclusion disease caused by inactivating mutations in MYO5B. Phenotypic patterns for aberrant apical trafficking are identified in patient tissue (duodenum). These patterns can be recapitulated in human patient-derived enteroids grown on Transwell filters in ALI conditions to induce differentiation (in vitro model). In ALI cultures, normal enterocytes demonstrate a dense actin-rich brush border, while MVID patient enteroid monolayers show disrupted microvillar structures. In vivo models of MYO5B deletion or loss-of-function also recapitulate the histology of MVID with the formation of microvillus inclusions and aberrant brush border structure (in SEM images, blue pseudo-coloring shows normal microvilli at left, while purple pseudocolor shows the presence of microvillus inclusion in MYO5B(G519R) mutant intestine). Reversal of aberrant phenotypes can then be used in vitro and in vivo to develop putative therapies.
Figure 3.
Figure 3.
Identification of apical bulk endocytosis in MYO5B knockout enterocytes. (A) MVID model mice (MYO5B knockout) show loss of actin-rich apical microvilli and formation of microvillus inclusions. Examination of these MYO5B KO mice showed that microvillus inclusions were formed through a process of apical bulk endocytosis. (B) Schematic summarizes the process of apical bulk endocytosis, which requires Pacsin 2 and dynamin 2 and involves the recruitment of tight junction proteins to the site of apical bulk endosome scission.
Figure 4.
Figure 4.
Evaluating the effects putative treatment in mouse models of MVID. Since disease in MVID affects the entire intestine, examination of the entire length of small intestine is required. The development of digital analysis tools to examine the localization of transporters (in this case SGLT1) in the villin and gamma-actin (ACTG)-rich brush border membranes allows quantitative evaluation of the effects of LPA treatment on the inducible, intestinal-targeted MYO5B knockout mice (MYO5BΔIEC). The panels at right demonstrate overlay images of SGLT1, villin, and apical area (red line) defined by the image math before and after treatment with lysophosphatidic acid (LPA) as a measure of treatment success. Scale bar = 20 µm.
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References

    1. Alsaleem, B.M.R., Ahmed A.B.M., and Fageeh M.A.. 2017. Microvillus inclusion disease variant in an infant with intractable diarrhea. Case Rep. Gastroenterol. 11:647–651. 10.1159/000479624 - DOI - PMC - PubMed
    1. Ameen, N.A., and Salas P.J.. 2000. Microvillus inclusion disease: A genetic defect affecting apical membrane protein traffic in intestinal epithelium. Traffic. 1:76–83. 10.1034/j.1600-0854.2000.010111.x - DOI - PubMed
    1. Babcock, S.J., Flores-Marin D., and Thiagarajah J.R.. 2023. The genetics of monogenic intestinal epithelial disorders. Hum. Genet. 142:613–654. 10.1007/s00439-022-02501-5 - DOI - PMC - PubMed
    1. Barker, N., van Es J.H., Kuipers J., Kujala P., van den Born M., Cozijnsen M., Haegebarth A., Korving J., Begthel H., Peters P.J., and Clevers H.. 2007. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature. 449:1003–1007. 10.1038/nature06196 - DOI - PubMed
    1. Booth, I.W., Stange G., Murer H., Fenton T.R., and Milla P.J.. 1985. Defective jejunal brush-border Na+/H+ exchange: A cause of congenital secretory diarrhoea. Lancet. 1:1066–1069. 10.1016/S0140-6736(85)92369-4 - DOI - PubMed

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