Transient architecture of the embryonic pancreas determines endocrine mass.

During organogenesis, epithelial tissues undergo extensive three-dimensional remodeling while simultaneously generating specialized cell types, yet whether transient architectural states actively instruct lineage allocation remains unclear. During pancreas development, de novo lumen formation transforms a stratified epithelium into a transient lumenal plexus from which endocrine, acinar and ductal lineages emerge. Here we identify the mechanosensitive Hippo pathway regulator Merlin as a critical link between epithelial architecture and cell fate. Loss of Merlin impairs de novo lumen formation, preventing epithelial destratification and establishment of the pancreatic plexus. Disruption of this architecture alters lineage allocation, impairing acinar differentiation and ultimately reducing adult endocrine cell mass and glucose homeostasis. Mosaic deletion reveals that these lineage defects arise non-cell autonomously, demonstrating that epithelial architecture itself instructs cell fate decisions. Mechanistically, Merlin coordinates polarized membrane trafficking to nascent lumens and restrains PI3K signaling; PI3K activation phenocopies Merlin loss, whereas PI3K inhibition partially rescues epithelial morphogenesis. Together, these findings establish the pancreatic plexus as an instructive developmental niche and reveal how transient tissue architecture can shape the cellular composition and function of mature organs.