The heterotrimeric basement membrane protein laminin-111 is essential for early mouse embryogenesis. Its beta1 and gamma1 chains are crucial for endoderm differentiation and for the formation of basement membranes, whereas alpha1 chain null mice only lack the extraembryonic Reichert's membrane. Nevertheless, mice deficient in the cell-binding alpha1 globular domains 4-5 (LG4-5) have a more severe phenotype than animals devoid of the whole alpha1 chain, as these domains are required for the formation of a polarized ectoderm. However, the influence of the alpha1LG4-5 domains on endoderm differentiation is unclear. We have used microarray analysis to compare the expression profiles of normal and alpha1LG4-5-deficient embryoid bodies and show that genes encoding secreted plasma proteins and proteins involved in endocytosis are reduced in alpha1LG4-5-deficient embryoid bodies, indicating incomplete differentiation of the visceral endoderm. Moreover, mice lacking alpha1LG4-5 display endoderm disorganization and a defective expression of the endoderm marker Dab2. We hypothesize that alpha1LG4-5 domains provide an autocrine signal necessary for the complete differentiation of a functional visceral endoderm and vital signals for the polarization of the epiblast.