Deficiency of the Tetraspanin CD63 Associated with Kidney Pathology but Normal Lysosomal Function

Abstract

CD63 is a member of the tetraspanin superfamily that constitutes a main component of the lysosomal membrane. In mice, two CD63 gene loci are present, with only one of these two being functional. We generated and analyzed mice deficient for active CD63. Disruption of CD63 results in a complete loss of CD63 protein expression. Despite its abundance in late endosomes/lysosomes, the lack of CD63 does not cause obvious endosomal/lysosomal abnormalities. CD63 knockout mice are viable and fertile without gross morphological abnormalities in the majority of tissues. No alterations in the populations of immune cells and only minor differences in platelet function were observed. This suggests that the lack of CD63 could be successfully compensated for, most likely by other tetraspanins. However, CD63 deficiency leads to an altered water balance. CD63 knockout mice show an increased urinary flow, water intake, reduced urine osmolality, and a higher fecal water content. In principle cells of the collecting duct of CD63-deficient mice, abnormal intracellular lamellar inclusions were observed. This indicates that the sorting of apical transport proteins might be impaired in these cells. CD63 knockout mice provide an important tool for analyzing the various postulated functions of CD63 in vivo.

Tetraspanin CD63 Promotes Vascular Endothelial Growth Factor Receptor 2-β1 Integrin Complex Formation, Thereby Regulating Activation and Downstream Signaling in Endothelial Cells in Vitro and in Vivo

“…1c) without causing morphological alterations in general or specifically of the late LAMP-1-positive endosomal/lysosomal compartment (Fig. 1d), in accordance with the literature (12). CD63 silencing.…”

“…Here, we show that endothelial cells in cd63 Ϫ/Ϫ mouse lungs failed to respond efficiently to VEGF stimulation, resulting in suppressed VEGFR2 activation and signaling. Still, CD63 knock-out mice survive embryonic development without overt signs of disturbed vascular development (12), possibly because of redundancy or functional compensation among different tetraspanin members or between different angiogenic pathways in a global CD63 knock-out. Clearly therefore, further studies of the consequence of conditional deletion of CD63 in ECs are warranted.…”

“…CD63 gene targeting in mice results in a relatively mild phenotype with increased gastrointestinal and kidney diuresis (12). Moreover, leukocyte attachment to cd63 Ϫ/Ϫ ECs is reduced because of altered trafficking of endothelial P-selectin, resulting in decreased leukocyte rolling and extravasation (13).…”

High susceptibility to fatty liver disease in two-pore channel 2-deficient mice

“…Immunocytochemistry was performed as described previously 58 . Histology, immunohistochemistry and electron microscopy experiments were performed according to standard protocols.…”

Tetraspanin Tspan9 regulates platelet collagen receptor GPVI lateral diffusion and activation

“…Mice deficient in either CD151 or Tspan32 have similar phenotypes, namely a partial defect in platelet aggregation and haemostasis that is proposed to be due to impaired outside-in signalling of the major platelet integrin αIIbβ3 [19–21]. Conversely, deficiency in either CD9 or CD63 causes a mildly hyperactive platelet phenotype without affecting haemostasis [22, 23]. CD82 deficiency results in more substantially hyperactive platelets, with enhanced haemostasis in vivo and enhanced clot retraction in vitro [24].…”