Stomach curvature is generated by left-right asymmetric gut morphogenesis

Abstract

Left-right (LR) asymmetry is a fundamental feature of internal anatomy, yet the emergence of morphological asymmetry remains one of the least understood phases of organogenesis. Asymmetric rotation of the intestine is directed by forces outside the gut, but the morphogenetic events that generate anatomical asymmetry in other regions of the digestive tract remain unknown. Here, we show in mouse and Xenopus that the mechanisms that drive the curvature of the stomach are intrinsic to the gut tube itself. The left wall of the primitive stomach expands more than the right wall, as the left epithelium becomes more polarized and undergoes radial rearrangement. These asymmetries exist across several species, and are dependent on LR patterning genes, including Foxj1, Nodal and Pitx2. Our findings have implications for how LR patterning manifests distinct types of morphological asymmetries in different contexts.

HCN4 ion channel function is required for early events that regulate anatomical left-right patterning in a Nodal- and Lefty asymmetric gene expression-independent manner

“…Previous studies have shown that Pitx2 plays two important roles during organogenesis; the left-sided expression in the lateral plate mesoderm is important for overall embryonic left-right determination, while the asymmetric (left side) expression within individual organ's tissues (particularly gut and heart) guides asymmetric morphogenesis of these organs ( Campione et al, 1999 ; Davis et al, 2017 ). Studies (both in mouse and Xenopus ) ( Clauss and Kaab, 2011 ; Davis et al, 2017 ; Poelmann et al, 2008 ) have shown that eliminating asymmetric Pitx2 expression within organs like heart and gut disrupts asymmetric organ morphogenesis and also leads to disrupted organ morphologies. In our studies, the reduced (but correctly-sided) Pitx2 signal in the lateral plate mesoderm may be affecting the Pitx2 expression in the heart and gut organs.…”

3D morphological analysis of spiral intestine morphogenesis in the little skate, Leucoraja erinacea

“…The break in symmetry is observed simultaneously at different orientations relative to the dorsal mesentery along the length of the developing intestine (Figure D‐D″). Thus, while the asymmetric morphology is reminiscent of that seen in the generation of the stomach curvature, it is not clear whether this asymmetry is related to left‐right (LR) identity …”

“…Thus, while the asymmetric morphology is reminiscent of that seen in the generation of the stomach curvature, it is not clear whether this asymmetry is related to left-right (LR) identity. 32 Naïve cells make up the epithelium and mesenchyme suggesting a rapid growth phase of the gut tube at this stage. Indeed, this rapid growth phase is reflected by the 4.5 spiral rotations seen at stage 27 ( Figure 2F).…”

“…37,38 The Nodal target gene Pitx2 is expressed on the left-side of developing organs and directs cell shape changes that lead to asymmetric organ morphologies in the gut. 32,39,40 In addition, Pitx2 directs cell shape changes in the dorsal mesentery that control the direction of gut looping. 27,28 Of interest, the break in symmetry observed at stage 25 is not strictly a LR event, as the Figure 1D-D 00 ).…”

Left–Right Patterning: Breaking Symmetry to Asymmetric Morphogenesis

“…By contrast, some asymmetries at the level of the stomach appear to rely more on endoderm-intrinsic mechanisms. For instance stomach curvature in mouse and Xenopus relies on asymmetries of tissue architecture and epithelial polarity of cells of the stomach itself, where Pitx2 is expressed in the left stomach wall only [30]. …”