@article{BurkardMeirKannapinetal.2021,
  author    = {Burkard, Natalie and Meir, Michael and Kannapin, Felix and Otto, Christoph and Petzke, Maximilian and Germer, Christoph-Thomas and Waschke, Jens and Schlegel, Nicolas},
  title     = {Desmoglein2 Regulates Claudin2 Expression by Sequestering PI-3-Kinase in Intestinal Epithelial Cells},
  series = {Frontiers in Immunology},
  volume    = {12},
  journal   = {Frontiers in Immunology},
  issn      = {1664-3224},
  doi       = {10.3389/fimmu.2021.756321},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-247059},
  year      = {2021},
  abstract  = {Inflammation-induced reduction of intestinal desmosomal cadherin Desmoglein 2 (Dsg2) is linked to changes of tight junctions (TJ) leading to impaired intestinal epithelial barrier (IEB) function by undefined mechanisms. We characterized the interplay between loss of Dsg2 and upregulation of pore-forming TJ protein Claudin2. Intraperitoneal application of Dsg2-stablising Tandem peptide (TP) attenuated impaired IEB function, reduction of Dsg2 and increased Claudin2 in DSS-induced colitis in C57Bl/6 mice. TP blocked loss of Dsg2-mediated adhesion and upregulation of Claudin2 in Caco2 cells challenged with TNFα. In Dsg2-deficient Caco2 cells basal expression of Claudin2 was increased which was paralleled by reduced transepithelial electrical resistance and by augmented phosphorylation of AKT\(^{Ser473}\) under basal conditions. Inhibition of phosphoinositid-3-kinase proved that PI-3-kinase/AKT-signaling is critical to upregulate Claudin2. In immunostaining PI-3-kinase dissociated from Dsg2 under inflammatory conditions. Immunoprecipitations and proximity ligation assays confirmed a direct interaction of Dsg2 and PI-3-kinase which was abrogated following TNFα application. In summary, Dsg2 regulates Claudin2 expression by sequestering PI-3-kinase to the cell borders in intestinal epithelium.},
  language  = {en}
}
@article{MeirKannapinDiefenbacheretal.2021,
  author    = {Meir, Michael and Kannapin, Felix and Diefenbacher, Markus and Ghoreishi, Yalda and Kollmann, Catherine and Flemming, Sven and Germer, Christoph-Thomas and Waschke, Jens and Leven, Patrick and Schneider, Reiner and Wehner, Sven and Burkard, Natalie and Schlegel, Nicolas},
  title     = {Intestinal epithelial barrier maturation by enteric glial cells is GDNF-dependent},
  series = {International Journal of Molecular Sciences},
  volume    = {22},
  journal   = {International Journal of Molecular Sciences},
  number    = {4},
  issn      = {1422-0067},
  doi       = {10.3390/ijms22041887},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-258913},
  year      = {2021},
  abstract  = {Enteric glial cells (EGCs) of the enteric nervous system are critically involved in the maintenance of intestinal epithelial barrier function (IEB). The underlying mechanisms remain undefined. Glial cell line-derived neurotrophic factor (GDNF) contributes to IEB maturation and may therefore be the predominant mediator of this process by EGCs. Using GFAP\(^{cre}\) x Ai14\(^{floxed}\) mice to isolate EGCs by Fluorescence-activated cell sorting (FACS), we confirmed that they synthesize GDNF in vivo as well as in primary cultures demonstrating that EGCs are a rich source of GDNF in vivo and in vitro. Co-culture of EGCs with Caco2 cells resulted in IEB maturation which was abrogated when GDNF was either depleted from EGC supernatants, or knocked down in EGCs or when the GDNF receptor RET was blocked. Further, TNFα-induced loss of IEB function in Caco2 cells and in organoids was attenuated by EGC supernatants or by recombinant GDNF. These barrier-protective effects were blunted when using supernatants from GDNF-deficient EGCs or by RET receptor blockade. Together, our data show that EGCs produce GDNF to maintain IEB function in vitro through the RET receptor.},
  language  = {en}
}
@article{KannapinSchmitzHansmannetal.2021,
  author    = {Kannapin, Felix and Schmitz, Tobias and Hansmann, Jan and Schlegel, Nicolas and Meir, Michael},
  title     = {Measurements of transepithelial electrical resistance (TEER) are affected by junctional length in immature epithelial monolayers},
  series = {Histochemistry and Cell Biology},
  volume    = {156},
  journal   = {Histochemistry and Cell Biology},
  number    = {6},
  issn      = {1432-119X},
  doi       = {10.1007/s00418-021-02026-4},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-267465},
  pages     = {609-616},
  year      = {2021},
  abstract  = {The measurement of transepithelial electrical resistance (TEER) is a common technique to determine the barrier integrity of epithelial cell monolayers. However, it is remarkable that absolute TEER values of similar cell types cultured under comparable conditions show an immense heterogeneity. Based on previous observations, we hypothesized that the heterogeneity of absolute TEER measurements can not only be explained by maturation of junctional proteins but rather by dynamics in the absolute length of cell junctions within monolayers. Therefore, we analyzed TEER in epithelial cell monolayers of Caco2 cells during their differentiation, with special emphasis on both changes in the junctional complex and overall cell morphology within monolayers. We found that in epithelial Caco2 monolayers TEER increased until confluency, then decreased for some time, which was then followed by an additional increase during junctional differentiation. In contrast, permeability of macromolecules measured at different time points as 4 kDA fluorescein isothiocyanate (FITC)-dextran flux across monolayers steadily decreased during this time. Detailed analysis suggested that this observation could be explained by alterations of junctional length along the cell borders within monolayers during differentiation. In conclusion, these observations confirmed that changes in cell numbers and consecutive increase of junctional length have a critical impact on TEER values, especially at stages of early confluency when junctions are immature.},
  language  = {en}
}
@article{MeirMaurusKuperetal.2021,
  author    = {Meir, Michael and Maurus, Katja and Kuper, Jochen and Hankir, Mohammed and Wardelmann, Eva and Rosenwald, Andreas and Germer, Christoph-Thomas and Wiegering, Armin},
  title     = {The novel KIT exon 11 germline mutation K558N is associated with gastrointestinal stromal tumor, mastocytosis, and seminoma development},
  series = {Genes, Chromosomes \& Cancer},
  volume    = {60},
  journal   = {Genes, Chromosomes \& Cancer},
  number    = {12},
  doi       = {10.1002/gcc.22988},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-257476},
  pages     = {827-832},
  year      = {2021},
  abstract  = {Familial gastrointestinal stromal tumors (GIST) are dominant genetic disorders that are caused by germline mutations of the type III receptor tyrosine kinase KIT. While sporadic mutations are frequently found in mastocytosis and GISTs, germline mutations of KIT have only been described in 39 families until now. We detected a novel germline mutation of KIT in exon 11 (p.Lys-558-Asn; K558N) in a patient from a kindred with several GISTs harboring different secondary somatic KIT mutations. Structural analysis suggests that the primary germline mutation alone is not sufficient to release the autoinhibitory region of KIT located in the transmembrane domain. Instead, the KIT kinase module becomes constitutively activated when K558N combines with different secondary somatic mutations. The identical germline mutation in combination with an additional somatic KIT mutation was detected in a second patient of the kindred with seminoma while a third patient within the family had a cutaneous mastocytosis. These findings suggest that the K558N mutation interferes with the juxtamembranous part of KIT, since seminoma and mastocystosis are usually not associated with exon 11 mutations.},
  language  = {en}
}