Basement membrane perforations guide anterior-posterior axis formation.

Abstract

Establishment of the anterior-posterior (AP) axis is a critical symmetry-breaking event in mammalian development. In mice, this process involves the directed migration of the distal visceral endoderm (DVE). Here, we use targeted perturbations to demonstrate that asymmetric perforations in the basement membrane guide DVE migration. During implantation, matrix metalloproteinases in extra-embryonic tissues create uneven basement membrane perforations, establishing directional cues for cohesive DVE migration. Using light-sheet microscopy and tissue cartography, we show that migrating DVE deforms surrounding tissues. Physical modeling and live imaging of DVE protrusions indicate that basement membrane perforations orchestrate active force generation within the DVE. Extending these findings to human embryos and stem cell-derived models, we identify basement membranes with enriched perforations near the anterior hypoblast in embryos, suggesting a conserved mechanism for AP axis specification. These findings reveal an unrecognized role of basement membrane remodeling and mechanical heterogeneity in guiding directional tissue migration during mammalian development.