Choreographed morphogenetic events underlie early foregut development in the mouse embryo

Abstract Between embryonic days 7.5 and 8.5, the mouse embryo undergoes a dramatic rearrangement of its entire anterior, a process known as ventral folding: the near-simultaneous morphogenesis of the cardiac crescent, cranial headfolds, and anterior foregut that together establish the antero-ventral body plan. While cardiac morphogenesis has been studied in detail, the cellular and mechanical basis of foregut involution remains largely undefined. Using combined light-sheet and spinning-disk live imaging spanning the full window of foregut formation, we show that involution proceeds through a stereotyped morphological programme that does not require actomyosin contractility for its initiation. Additionally, involution is preceded by a spatiotemporally restricted wave of apoptosis in embryonic visceral endoderm (emVE) cells, which extrude bidirectionally. A lineage- and stage-resolved bulk RNA-sequencing of emVE, definitive endoderm, and epiblast populations identifies a differential-adhesion and cell-cycle signature underlying this behaviour. Revisiting a visceral-endoderm-specific Bmp2 knock-out mutant, we find that BMP2 controls involution indirectly, by directing notochord positioning and thereby the geometry of the surrounding heart and headfold mechanics. Together, these findings reframe ventral folding as a single coordinated geometric process rather than a set of independent organ forming events.