Publications by authors named "Aparna Mahadevan"

4 Publications

  • Page 1 of 1

The asymmetric Pitx2 gene regulates gut muscular-lacteal development and protects against fatty liver disease.

Cell Rep 2021 Nov;37(8):110030

Department of Molecular Medicine, College of Veterinary Medicine, Cornell, Ithaca, NY 14853, USA. Electronic address:

Intestinal lacteals are essential lymphatic channels for absorption and transport of dietary lipids and drive the pathogenesis of debilitating metabolic diseases. However, organ-specific mechanisms linking lymphatic dysfunction to disease etiology remain largely unknown. In this study, we uncover an intestinal lymphatic program that is linked to the left-right (LR) asymmetric transcription factor Pitx2. We show that deletion of the asymmetric Pitx2 enhancer ASE alters normal lacteal development through the lacteal-associated contractile smooth muscle lineage. ASE deletion leads to abnormal muscle morphogenesis induced by oxidative stress, resulting in impaired lacteal extension and defective lymphatic system-dependent lipid transport. Surprisingly, activation of lymphatic system-independent trafficking directs dietary lipids from the gut directly to the liver, causing diet-induced fatty liver disease. Our study reveals the molecular mechanism linking gut lymphatic function to the earliest symmetry-breaking Pitx2 and highlights the important relationship between intestinal lymphangiogenesis and the gut-liver axis.
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http://dx.doi.org/10.1016/j.celrep.2021.110030DOI Listing
November 2021

Distinct cellular roles for PDCD10 define a gut-brain axis in cerebral cavernous malformation.

Sci Transl Med 2019 11;11(520)

Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.

Cerebral cavernous malformation (CCM) is a genetic, cerebrovascular disease. Familial CCM is caused by genetic mutations in , , or Disease onset is earlier and more severe in individuals with mutations. Recent studies have shown that lesions arise from excess mitogen-activated protein kinase kinase kinase 3 (MEKK3) signaling downstream of Toll-like receptor 4 (TLR4) stimulation by lipopolysaccharide derived from the gut microbiome. These findings suggest a gut-brain CCM disease axis but fail to define it or explain the poor prognosis of patients with mutations. Here, we demonstrate that the gut barrier is a primary determinant of CCM disease course, independent of microbiome configuration, that explains the increased severity of CCM disease associated with PDCD10 deficiency. Chemical disruption of the gut barrier with dextran sulfate sodium augments CCM formation in a mouse model, as does genetic loss of , but not , in gut epithelial cells. Loss of gut epithelial results in disruption of the colonic mucosal barrier. Accordingly, loss of Mucin-2 or exposure to dietary emulsifiers that reduce the mucus barrier increases CCM burden analogous to loss of in the gut epithelium. Last, we show that treatment with dexamethasone potently inhibits CCM formation in mice because of the combined effect of action at both brain endothelial cells and gut epithelial cells. These studies define a gut-brain disease axis in an experimental model of CCM in which a single gene is required for two critical components: gut epithelial function and brain endothelial signaling.
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http://dx.doi.org/10.1126/scitranslmed.aaw3521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937779PMC
November 2019

Midgut Laterality Is Driven by Hyaluronan on the Right.

Dev Cell 2018 09 30;46(5):533-551.e5. Epub 2018 Aug 30.

Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.devcel.2018.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207194PMC
September 2018

The left-right Pitx2 pathway drives organ-specific arterial and lymphatic development in the intestine.

Dev Cell 2014 Dec 4;31(6):690-706. Epub 2014 Dec 4.

Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA. Electronic address:

The dorsal mesentery (DM) is the major conduit for blood and lymphatic vessels in the gut. The mechanisms underlying their morphogenesis are challenging to study and remain unknown. Here we show that arteriogenesis in the DM begins during gut rotation and proceeds strictly on the left side, dependent on the Pitx2 target gene Cxcl12. Although competent Cxcr4-positive angioblasts are present on the right, they fail to form vessels and progressively emigrate. Surprisingly, gut lymphatics also initiate in the left DM and arise only after-and dependent on-arteriogenesis, implicating arteries as drivers of gut lymphangiogenesis. Our data begin to unravel the origin of two distinct vascular systems and demonstrate how early left-right molecular asymmetries are translated into organ-specific vascular patterns. We propose a dual origin of gut lymphangiogenesis in which prior arterial growth is required to initiate local lymphatics that only subsequently connect to the vascular system.
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http://dx.doi.org/10.1016/j.devcel.2014.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326534PMC
December 2014
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