A self-limiting mechanotransduction feedback loop ensures robust organ formation

Abstract Organ development requires integration of mechanical forces, biochemical signals, and transcriptional programs to achieve proper size and architecture. Mechanotransduction feedback loops convert mechanical forces into gene-expression changes that, in turn, regulate cell behaviors such as growth and extracellular matrix (ECM) production. How these loops are coupled to developmental programs to ensure robust morphogenetic outcomes remains poorly understood. Here, we show that Yap-dependent mechanotransduction establishes a self-limiting positive feedback loop that drives the successful formation of semicircular canals in zebrafish. These canals form through reproducible steps of bud initiation, extension, and fusion within the otic epithelium. Local swelling of a hyaluronan-rich ECM initiates bud formation. We demonstrate that this ECM expansion activates Yap in a spatially patterned manner within the bud. Activated Yap induces its target, ccn1l1, which drives further ECM production, establishing a positive feedback loop. The ensuing rapid ECM expansion sustains bud extension. Graded perturbations to the mechanotransduction loop reduced extension, with bud fusion remaining robust at lower levels of disruption but blocked at the highest dose. Critically, the loop contains its own termination mechanism: when buds fuse, the PKA-CREB signaling is activated by the adhesion GPCR Gpr126 to suppress ccn1l1, preventing overgrowth. These findings reveal how mechanotransduction-driven positive feedback loops can be coupled to their own termination, providing developmental control through the integration of mechanical forces with transcriptional responses and morphogenetic outcomes.