Transcriptional coupling of metabolism and cell mechanics controls humanneuroepithelium morphogenesis

Abstract

Tissue morphogenesis integrates developmental programs with cell mechanics, yet the mechanisms coupling these processes remain poorly understood. We investigated this link during neuroepithelial morphogenesis in human iPSC-derived dorsal spinal organoids. We found that PAX3, a transcription factor whose loss causes neural tube defects, promotes force-bearing adherens junction assembly. It does so by driving apical clustering of N-cadherin complexes, thereby enabling neuroepithelial morphogenesis, a function conserved in the mouse neural tube. Transcriptomic, metabolomic, and functional analyses show that PAX3 sustains upper glycolysis and the associated mannose-dependent glycosylation pathways. Exogenous mannose rescues cadherin clustering and adherens junction mechanics following PAX3 loss, whereas inhibition of glycolysis or glycosylation recapitulates these defects. These findings establish mannose metabolism as a PAX3-regulated pathway conferring mechanical competence to developing tissues.