Mouse Models of Human Claudin-Associated Disorders: Benefits and Limitations

Abstract

In higher organisms, epithelia separate compartments in order to guarantee their proper function. Such structures are able to seal but also to allow substances to pass. Within the paracellular pathway, a supramolecular structure, the tight junction transport is largely controlled by the temporospatial regulation of its major protein family called claudins. Besides the fact that the expression of claudins has been identified in different forms of human diseases like cancer, clearly defined mutations in the corresponding claudin genes have been shown to cause distinct human disorders. Such disorders comprise the skin and its adjacent structures, liver, kidney, the inner ear, and the eye. From the phenotype analysis, it has also become clear that different claudins can cause a complex phenotype when expressed in different organs. To gain deeper insights into the physiology and pathophysiology of claudin-associated disorders, several mouse models have been generated. In order to model human disorders in detail, they have been designed either as full knockouts, knock-downs or knock-ins by a variety of techniques. Here, we review human disorders caused by CLDN mutations and their corresponding mouse models that have been generated thus far and assess their usefulness as a model for the corresponding human disorder.

Claudin-1, A Double-Edged Sword in Cancer

“…Although both renal disorders FHHN and CINF are caused by PCLN-1/CLDN16 mutations, but the clinical features of both diseases are quite different which may be due to specific mutations/deletions in the same gene or through species specificity. Since the first report [153], several other tight junction disorders have been shown to cause human diseases including mutations in claudin proteins such as CLDN-1 [156], CLDN-9 [157], , CLDN-14 [159], CLDN-16 [160], CLDN-19 [161] (for detailed reviews see [162]).…”

Heterocellular spheroids of the neurovascular blood-brain barrier as a platform for personalized nanoneuromedicine

“…In endothelial cell 2D monocultures, the expression of CLDN genes was in general lower than that in both 3D systems except for CLDN1, CLDN11, and CLDN12 (Figures 6A and 6F). In all the systems, the expression of CLDN1, CLDN2, CLDN3, CLDN4, CLDN6, CLDN7, CLDN8, CLDN9, CLDN11, CLDN14, CLDN16, CLDN17, CLDN18, and CLDN20 transcripts was relatively low (Figures 6A and 6F); these genes are more specific of epithelial (and not endothelial) tight junctions (Garcia-Hernandez et al, 2017;Gü nzel and Yu, 2013;Seker et al, 2019;Wolburg et al, 2001). A relatively high level of CLDN15 could be observed in endothelial cell monocultures, while CLDN19 expression was detected in the 2D endothelial cell model but not in 3D spheroids (Figures 6A and 6B).…”

Special Issue on “The Tight Junction and Its Proteins: More than Just a Barrier”

“…To study the function and impact of single TJ proteins in such complexity, often, mouse models are generated that can provide information on human-associated disorders. Such models may be knock-outs, knock-downs, or knock-ins of the respective proteins [ 26 ], and the findings can be related to observed pathologies in patients. However, interspecific differences need to be taken in account, which, for example, can be observed in intestinal preservation injury, where progression at the tissue and molecular levels differs between rats, pigs, and humans [ 27 ].…”