Absence of the tight junctional protein AF-6 disrupts epithelial cell-celljunctions and cell polarity during mouse development

Background: The establishment, maintenance and rearrangement of junctions b etween epithelial cells are extremely important in many developmental, phys iological and pathological processes. AF-6 is a putative Ras effector; it i s also a component of tight and adherens junctions, and has been shown to b ind both Ras and the tight-junction protein ZO-1. In the mouse, AF-6 is enc oded by the Af6 gene. As cell-cell junctions are important in morphogenesis , we generated a null mutation in the murine Af6 locus to test the hypothes is that lack of AF-6 function would cause epithelial abnormalities. Results: Although cell-cell junctions are thought to be important in early embryogenesis, homozygous mutant embryos were morphologically indistinguish able from wild-type embryos through 6.5 days post coitum (dpc) and were abl e to establish all three germ layers. The earliest morphological abnormalit ies were observed in the embryonic ectoderm of mutant embryos at 7.5 dpc. T he length of the most apical cell-cell junctions was reduced, and basolater al surfaces of those cells were separated by multiple gaps. Cells of the em bryonic ectoderm were less polarized as assessed by histological criteria a nd lateral localization of an apical marker. Mutant embryos died by 10 dpc, probably as a result of placental failure. Conclusions: AF-6 is a critical regulator of cell-cell junctions during mou se development. The loss of neuroepithelial polarity in mutants is consiste nt with a loss of efficacy of the cell-cell junctions that have a critical role in establishing apical/basolateral asymmetry.