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THE LEFT-RIGHT ASYMMETRY TRANSCRIPTION FACTOR PITX2 REGULATES INTESTINAL LYMPHATIC DEVELOPMENT AND FUNCTION

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2024-06-02
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The mammalian intestinal lymphatic system is specialized for efficient dietary lipid uptake. Intestinal lymphatic development initiates in the embryo, in preparation for a postnatal fat-rich diet of milk. However, the functional and developmental regulation of the intestinal lymphatic system, particularly during the late embryonic to early neonatal period, remains largely unknown. My research focuses on filling the knowledge gap at this critical developmental transition when intestinal lymphatic function is established to ensure postnatal homeostasis. Intestinal dietary lipid transport is together accomplished by the lymphatic-dependent and the lymphatic-independent pathways. The former is the major lipid transport route in mammals that handles larger lipid molecules, while the latter is responsible for transporting smaller molecules directly to the liver from the villous blood capillaries into the portal vein. The activation of these two lipid transport pathways is finely regulated by dietary lipids and other physiological factors such as age, gender, and disease. Importantly, the lymphatic-independent transport can compensate for the lymphatic-dependent transport when the latter is functionally compromised. Such compensation ensures efficient lipid trafficking but risks liver injury by introducing massive lipids and intestine-derived antigens to the liver. In addition, the two transport pathways deliver lipids to different body compartments. Knowledge of the regulatory mechanisms between the two lipid transport pathways has successfully opened pharmaceutical opportunities to improve drug delivery precision and efficiency. We unexpectedly discovered that the left-right axis determining transcription factor Pitx2 is critical for proper intestinal lymphatic development and lipid transport function. Pitx2 null mice show intestinal lymphatic agenesis, while mutant mice lacking the left side isoform Pitx2c enhancer Asymmetric element (ASE) display abnormal intestinal lymphatic development. This is caused by oxidative damage in the adjacent Pitx2-dependent smooth muscle cells, which regulate intestinal lymphatic development and function. Consequently, pathological activation of lymphatic-independent lipid transport accumulates massive lipids in the liver resulting in fatty liver disease in the neonates. Published on the cover of Cell Reports (Hu et al., 2021), this is one of the very few fatty liver disease animal models available that does not rely on high fat diet induction, and the first report of the role of the LR Pitx2 in lipid transport function. To identify the cellular and molecular basis of the above Pitx2-dependent gut lymphatic phenotypes, we conducted two single cell transcriptomic analyses in the prenatal and neonatal intestines. In the first analysis, we compared gene expression patterns in WT vs. ASE mutant. In the second analysis, we compared Pitx2c-dependent vs. Pitx2c-independent cell linages using kerflop recombination combined with single cell sequencing. Surprising, we learned that in addition to intestinal smooth muscle cells, a population of mesothelial and blood capillary endothelial cells are also derived from a Pitx2 lineage. The ongoing work focuses on understanding the specific roles of Pitx2 in different cell lineages, with the aim of parsing out the cellular mechanisms that pathologically activate the lymphatic-independent lipid transport in our mouse model.

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320 pages

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2022-05

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fatty liver disease; intestinal lipid transport; intestinal lymphatics; intestinal muscle; left-right asymmetry; Pitx2

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Kurpios, Natasza

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Simoes-Costa, Marcos
Danko, Charles G.
Hollopeter, Gunther

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Biomedical and Biological Sciences

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Ph. D., Biomedical and Biological Sciences

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Doctor of Philosophy

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dissertation or thesis

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