Mechanical Regulation of Three-Dimensional Epithelial Fold Pattern Formation in the Mouse Oviduct

Abstract

Epithelia exhibit various three-dimensional morphologies linked to organ function in animals. However, the mechanisms of three-dimensional morphogenesis remain elusive. The luminal epithelium of the mouse oviduct forms well-aligned straight folds along the longitudinal direction of the tubes. Disruption of the Celsr1 gene, a planar cell polarity-related gene, causes ectopically branched folds. Here, we evaluated the mechanical contributions of the epithelium to the fold pattern formation. In the mutant oviduct, the epithelium was more intricate along the longitudinal direction than in the wild-type, suggesting a higher ratio of the longitudinal length of the epithelial layer to that of the surrounding smooth muscle (SM) layer (L-Epi/SM ratio). Our mathematical modeling and computational simulations suggested that the L-Epi/SM ratio could explain the differences in fold branching between the two genotypes. Longitudinal epithelial tensions were increased in well-aligned folds compared with those in disorganized folds both in the simulations and in experimental estimations. Artificially increasing the epithelial tensions suppressed the branching in simulations, suggesting that the epithelial tensions can regulate fold patterning. The epithelial tensions could be explained by the combination of line tensions along the epithelial cell-cell boundaries with the polarized cell arrays observed in vivo. These results suggest that the fold pattern is associated with the polarized cell array through the longitudinal epithelial tension. Further simulations indicated that the L-Epi/SM ratio could contribute to fold pattern diversity, suggesting that the L-Epi/SM ratio is a critical parameter in the fold patterning in tubular organs.

Smooth muscle: a stiff sculptor of epithelial shapes

“…This model could also recapitulate the folding pattern in Celsr1-knockout mice by increasing the longitudinal length of the epithelium relative to its constraining cylinder. Adding support for this mechanical viewpoint, laser ablation experiments confirmed that the wild-type epithelium retracts more than the mutant in the longitudinal direction, indicating that the mutant is under lower longitudinal tension, as would be expected if the complex folds of the knockout were due to longitudinal compression of the epithelium [7]. This simple model can further recapitulate diverse and complex folding patterns by modifying the circumference and length of the epithelium relative to its constraining cylinder [7].…”

“…The adult mouse oviduct changes its shape and folding pattern during ovulation. Since the smooth muscle layer does not fold along with the epithelium, the circumferential length of the epithelium is greater than that of the smooth muscle, suggesting that the epithelial folds form through a buckling mechanism induced by the surrounding smooth muscle [7]. Knocking out the planar cell polarity gene Celsr1 leads to disordered alignment of epithelial cells, disordered folding in the longitudinal direction and the development of some circumferential folds.…”

BMP signaling controls buckling forces to modulate looping morphogenesis of the gut

“…intestinal looping | buckling | biomechanics | Bmp | morphogenesis D ifferential growth represents one of the core physical mechanisms driving morphogenesis throughout the vertebrate embryo (1)(2)(3)(4)(5)(6)(7)(8)(9). Investigations into the mechanics of differential growth have often illustrated key physical parameters (e.g., tissue stiffness, growth rates, and initial geometry) that determine the resultant tissue shape.…”

Generating tissue topology through remodeling of cell-cell adhesions

“…PCP is required to create a polarized network in which cells are elongated along the length of the tube; this allows for increased tissue-level tension along that axis, yielding well-aligned folds. Loss of Celsr1 abrogates cell elongation and reduces longitudinal tension, leading to misaligned folds [14, 15]. …”