Midgut Laterality Is Driven by Hyaluronan on the Right.

Area of Science:

• Developmental Biology
• Molecular Biology
• Biochemistry

Background:

• The left-right asymmetry of organs in vertebrates has been primarily attributed to the Pitx2 gene on the left side of the embryo.
• A comprehensive understanding of all molecular pathways governing organ laterality, especially those initiated from the right side, remains incomplete.

Purpose of the Study:

• To identify and characterize a novel pathway regulating left-right body asymmetry initiated from the right side of the embryo.
• To investigate the role of extracellular matrix components, specifically hyaluronan (HA), and associated enzymes in embryonic organ development and laterality.

Main Methods:

• Investigated the role of hyaluronan (HA) and the enzyme Tsg6 in embryonic development using chicken embryos and Tsg6 knockout mice.
• Analyzed the effects of HA disruption and Tsg6 deficiency on midgut rotation and gut vasculature patterning.
• Examined cell behavior in response to modified HA matrices.

Main Results:

• Identified a right-side initiated pathway for left-right asymmetry orchestrated by the extracellular glycosaminoglycan hyaluronan (HA), independent of Pitx2.
• Demonstrated that covalent modification of HA by the enzyme Tsg6 on the right side triggers specific cell behaviors essential for midgut rotation and gut vascular patterning.
• Showed that disruption of HA or Tsg6 leads to failed midgut rotation and perturbed vascular development, predisposing to midgut volvulus.

Conclusions:

• The study reveals a conserved mechanism for organ laterality initiated from the right side of the embryo, involving Tsg6-mediated modification of HA.
• This finding challenges the existing paradigm of symmetry-breaking in vertebrates, highlighting the critical role of enzymatic modification of HA matrices in establishing organ laterality.
• The research provides new insights into the molecular basis of midgut development and offers potential targets for understanding and treating related congenital disorders.