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Left, Right, and Center: A Novel Midline Barrier Separates Asymmetric Extracellular Matrix During Intestinal Development

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2024-09-05
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Abstract

Correct intestinal morphogenesis depends on the early embryonic process of gut rotation, an evolutionarily-conserved program in which a straight gut tube elongates and forms into its first loops. The gut tube requires guidance to loop reproducibly, however. The dorsal mesentery (DM) connects the gut tube to the rest of the body and directs the lengthening gut into these loops via left-right asymmetric cellular and extracellular behavior. Specifically, expansion of the extracellular matrix in the right DM and condensation of the left side drives a leftward tilt to set up the first gut loop. Vascular patterning also occurs asymmetrically with a left-sided bias. These asymmetries depend on a simple sugar, hyaluronan (HA), which is found throughout the DM but is covalently modified by the enzyme TSG6 only on the right side, causing expansion and vascular exclusion. Left-sided HA is unmodified, pro-vascular, and bound to the proteoglycan versican. When these asymmetries and gut tilting are perturbed, the organism is at risk for volvulus, a catastrophic self-strangulation of the gut tube.The role of versican in gut morphogenesis is highly understudied, although it is known to be critical for organ morphogenesis and smooth muscle development in other contexts. I determined that versican localizes to the blood vasculature within the DM and the smooth muscle of the intestinal wall, and that this versican is cleaved by ADAMTS enzymes. ADAMTS enzymes create bioactive fragments of versican which have diverse impacts on development. While the role of versican and its cleavage in gut development is still unknown, my characterizations and preliminary experiments with conditional knockout mouse lines can inform future experiments to understand how versican is implicated in vascular and intestinal smooth muscle development. Although the right and left DM asymmetrically express many genes, including some which encode morphogens, a physical or molecular separation between the two sides has not been described previously. The early embryo requires a Lefty1-positive midline barrier to specify the left-right body axis, without which embryos suffer lethal or congenital patterning defects. Many individual organs also have left-right asymmetry, but only the brain has a known mechanism for separating the two sides. We identified a novel midline barrier in the DM which transiently divides left and right during developmental stages when DM asymmetries are being established. The DM midline does not express Lefty1 and is instead composed of an atypical double basement membrane, which prevents movement of diffusible dextran between the two sides. This basement membrane does not arise from the DM mesenchyme or from epithelial- to-mesenchymal transition of the endoderm, and the notochord is not sufficient for its synthesis. Although the function of the midline could not be evaluated with any of the attempted ablation efforts, we predict that the DM midline barrier forms a functional boundary between the left and right sides which is necessary for the establishment and protection of intestinal asymmetry.

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201 pages

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2023-08

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basement membrane; dorsal mesentery; extracellular matrix; intestinal development; midline barrier

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Kurpios, Natasza

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Reesink, Heidi
Fischbach, Claudia
Simoes Costa, Marcos

Degree Discipline

Genetics, Genomics and Development

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Ph. D., Genetics, Genomics and Development

Degree Level

Doctor of Philosophy

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dissertation or thesis

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