Mechanisms of regional morphogenesis along the gastrointestinal tract

Abstract

Distinct compartments along the gastrointestinal tract perform complementary digestive processes that sustain life. In vertebrates, the esophagus, small intestine, and large intestine originate from a common primordial gut tube, but eventually adopt unique forms consistent with their roles in digestion. Despite our extensive knowledge of conserved molecular factors that specify anteroposterior gut regions, the physical processes that differentially shape them are virtually unknown. Furthermore, how these regional genes regulate mechanical forces to confer distinct morphologies is poorly understood. This thesis presents three sets of findings from the developing chick gut that address how intestinal identity regulates form. First, we asked how compartments achieve specialized tube dimensions. By combining smFISH, cell division and density measurements, and predictions from a two-step mathematical model of reaction-diffusion based patterning followed by growth, we found that volumetric growth parameters predict growth trajectories well, but gene expression data do not match model predictions. Explant experiments instead suggest that differential sensitivities to Bmp and Shh signaling along the gut define muscle patterns. Thus, both morphogen patterning and growth are important for specifying early gut tube dimensions. Proper morphogenesis of the gut epithelium is important for function in all compartments, so we next asked how the esophagus and large intestine develop distinct lumen wrinkling patterns from the midgut by measuring growth and mechanical parameters during initial epithelial diversification. Systematic simulations incorporating these data show that spatiotemporal geometries, stiffnesses, and growth rates control both primary and secondary, multiscale buckling patterns found in the foregut and hindgut. Finally, gut compartment identities are demarcated early in development via Hox genes, which are highly conserved, master regulators of spatial patterning in the embryo that were discovered 30 years ago in vertebrates; yet, how these factors trigger regional morphogenesis is still a mystery. We combined mechanical measurements and mathematical modeling to demonstrate that the posterior Hox gene Hoxd13 regulates biophysical phenomena that shape the hindgut lumen. We further show that Hoxd13 acts through the TGFβ pathway to thicken, stiffen, and promote isotropic growth of the subepithelial mesenchyme; together, these features generate hindgut surface patterns. TGFβ, in turn, promotes collagen deposition to affect mesenchymal geometry and growth. We thus identify a cascade of events downstream of genetic identity that direct posterior intestinal morphogenesis.