The Lego hypothesis of tissue morphogenesis: stereotypic organization of parallel orientational cell adhesions for epithelial self-assembly.

How tissues develop distinct structures remains poorly understood. We propose herein the Lego hypothesis of tissue morphogenesis, which states that during tissue morphogenesis, the topographical properties of cell surface adhesion molecules can be dynamically altered and polarised by regulating the spatiotemporal expression and localization of orientational cell adhesion (OCA) molecules cell-autonomously and non-cell-autonomously, thus modulating cells into unique Lego pieces for self-assembling into distinct cytoarchitectures. This concept can be exemplified by epithelial morphogenesis, in which cells are coalesced into a sheet by many types of adhesions. Among them, parallel OCAs (pOCAs) at the lateral cell membranes are essential for configuring cells in parallel. Major pOCAs include Na⁺/K⁺-ATPase-mediated adhesions, Crumbs-mediated adhesions, tight junctions, adherens junctions, and desmosomes. These pOCAs align in stereotypical orders along the apical-to-basal axis, and their absolute positioning is also regulated. Such spatial organization of pOCAs underlies proper epithelial morphogenesis. Thus, a key open question about tissue morphogenesis is how to regulate OCAs to make compatible adhesive cellular Lego pieces for tissue construction.