Midgut Laterality Is Driven by Hyaluronan on the Right

Abstract

For many years, biologists have focused on the role of Pitx2, expressed on the left side of developing embryos, in governing organ laterality. Here, we identify a different pathway during left-right asymmetry initiated by the right side of the embryo. Surprisingly, this conserved mechanism is orchestrated by the extracellular glycosaminoglycan, hyaluronan (HA) and is independent of Pitx2 on the left. Whereas HA is normally synthesized bilaterally as a simple polysaccharide, we show that covalent modification of HA by the enzyme Tsg6 on the right triggers distinct cell behavior necessary to drive the conserved midgut rotation and to pattern gut vasculature. HA disruption in chicken and Tsg6 mice results in failure to initiate midgut rotation and perturbs vascular development predisposing to midgut volvulus. Our study leads us to revise the current symmetry-breaking paradigm in vertebrates and demonstrates how enzymatic modification of HA matrices can execute the blueprint of organ laterality.

Molecular and cellular basis of left–right asymmetry in vertebrates

“…Covalent modification of the extracellular matrix component hyaluronan by Tsg6 takes place on the right side of chick and mouse embryos, and this modification is essential for midgut looping. 123 ) Tsg6 is expressed in the dorsal mesentery on the right side of chick embryos, and Tsg6 mutant mice manifest aberrant rotation of the midgut. 123 ) The precise relation between the Nodal-Pitx2 pathway and the Tsg6-hyaluronan pathway remains to be clarified.…”

“… 123 ) Tsg6 is expressed in the dorsal mesentery on the right side of chick embryos, and Tsg6 mutant mice manifest aberrant rotation of the midgut. 123 ) The precise relation between the Nodal-Pitx2 pathway and the Tsg6-hyaluronan pathway remains to be clarified.…”

“…Cellular changes that initiate L-R asymmetry in the midgut tube of the chick embryo. 120 , 123 ) Asymmetries arise in the dorsal mesentery between Hamburger–Hamilton (HH) stages 20 and 22. Left side-specific Nodal-Pitx2 expression drives compaction of mesenchymal cells (green rectangles) within the left dorsal mesentery and promotes retention of a columnar morphology of epithelial cells (blue rectangles) on the left side of the dorsal mesentery.…”

Transient Nodal signalling in left precursors coordinates opposed asymmetries shaping the heart loop

“…Nodal is not always required for asymmetric organogenesis, as shown in the fly (see Coutelis et al, 2014;Spéder et al, 2006). Other determinants than Nodal have been identified, for example on the right side (Ocaña et al, 2017;Sivakumar et al, 2018) or acting in parallel (Pai et al, 2017).…”

Strong reduction of the chain rigidity of hyaluronan by selective binding of Ca2+ions

“…Alone or together with other extracellular matrix macromolecules (e.g., collagen), it dictates tissue elasticity, hydration and permeability, and it also directs cell behavior through multivalent engagement with cell surface receptors, such as CD44. 14 These properties allow HA to mediate diverse functions in a wide range of physiological and pathological processes, including development, 15,16 mammalian reproduction, 17 inflammation, 18 and tissue lubrication. 19,20 Diseases such as cancer or osteoarthritis are correlated with changes in the average molecular weight, supramolecular organization and concentration of hyaluronan.…”