Dystroglycan is essential for early embryonic development: disruption of Reichert's membrane in Dag1-null mice

Dystroglycan is a central component of the dystrophin-glycoprotein complex(DGC), a protein assembly that plays a critical role in a variety ofmuscular dystrophies. In order to better understand the function ofdystroglycan in development and disease, we have generated a null allele ofdystroglycan (Dag1neo2) in mice. Heterozygous Dag1neo2 mice are viable andfertile. In contrast, homozygous Dag1neo2 embryos exhibit grossdevelopmental abnormalities beginning around 6.5 days of gestation.Analysis of the mutant phenotype indicates that an early defect in thedevelopment of homozygous Dag1neo2 embryos is a disruption of Reichert'smembrane, an extra-embryonic basement membrane. Consistent with thefunctional defects observed in Reichert's membrane, dystroglycan protein islocalized in apposition to this structure in normal egg cylinder stageembryos. We also show that the localization of two critical structuralelements of Reichert's membrane- -laminin and collagen IV--are specificallydisrupted in the homozygous Dag1neo2 embryos. Taken together, the dataindicate that dystroglycan is required for the development of Reichert'smembrane. Furthermore, these results suggest that disruption of basementmembrane organization might be a common feature of muscular dystrophieslinked to the DGC.