DYSTROGLYCAN IS ESSENTIAL FOR EARLY EMBRYONIC-DEVELOPMENT - DISRUPTION OF REICHERTS-MEMBRANE IN DAG1-NULL MICE

Dystroglycan is a central component of the dystrophin-glycoprotein com plex (DGC), a protein assembly that plays a critical role in a variety of muscular dystrophies. In order to better understand the function o f dystroglycan in development and disease, we have generated a null al lele of dystroglycan (Dag1(neo2)) in mice. Heterozygous Dag1(neo2) mic e are viable and fertile. In contrast, homozygous Dag1(neo2) embryos e xhibit gross developmental abnormalities beginning around 6.5 days of gestation, Analysis of the mutant phenotype indicates that an early de fect in the development of homozygous Dag1(neo2) embryos is a disrupti on of Reichert's membrane, an extra-embryonic basement membrane. Consi stent with the functional defects observed in Reichert's membrane, dys troglycan protein is localized in apposition to this structure in norm al egg cylinder stage embryos. We also show that the localization of t wo critical structural elements of Reichert's membrane-laminin and col lagen IV-are specifically disrupted in the homozygous Dag1(neo2) embry os. Taken together, the data indicate that dystroglycan is required fo r the development of Reichert's membrane. Furthermore, these results s uggest that disruption of basement membrane organization might be a co mmon feature of muscular dystrophies linked to the DGC.