Mucin-type O-glycosylation is an evolutionarily conserved protein modification. It presents abundantly on membrane and secreted proteins with largely unknown biological functions. Using genetically engineered mouse models, our previous studies revealed new fundamental roles of O-glycosylation in angiogenesis and lymphangiogenesis, which are essential vascular processes in health and disease. We discovered that mice lacking endothelial O-glycans develop a blood-lymphatic mixing phenotype and fatty liver disease. Moreover, we demonstrated that O-glycoprotein podoplanin requires proper O-glycosylation to bind to and activate its receptor CLEC-2 on platelets, by which it governs the blood-lymphatic separation during embryonic development and maintains its integrity throughout life. Besides blood-lymphatic misconnections, we found that mice deficient in podoplanin-CLEC-2 signaling pathway exhibit brain-specific hemorrhage during embryonic development, which highly resembles germinal matrix hemorrhage affecting nearly 30% of preterm infants.
My current research is centered on understanding the molecular mechanisms underlying the vascular defects in mice with deficiencies of O-glycans or O-glycoproteins. We are investigating how podoplanin-CLEC-2 axis regulates lymphovenous homeostasis and how lack of podoplanin or CLEC-2 results in bleeding in the developing mouse brain. Our long-term goal is to translate the knowledge developed through our research into effective preventions or therapies of human diseases.
M.D., Zhenjiang Medical College, P.R. China, 1993
M.S., Suzhou Medical College, P.R. China, 1998
Ph.D., Soochow University, P.R. China, 2003
Joined OMRF Scientific Staff in 2003
Bergstrom K, Fu J, Johansson ME, Liu X, Gao N, Wu Q, Song J, McDaniel JM, McGee S, Chen W, Braun J, Hansson GC, Xia L. Core 1- and 3-derived O-glycans collectively maintain the colonic mucus barrier and protect against spontaneous colitis in mice. Mucosal Immunol. 2016 May 4. [Epub ahead of print]. [Abstract] PMID: 27143302.
Cha B, Geng X, Mahamud MR, Fu J, Mukherjee A, Kim Y, Jho EH, Kim TH, Kahn ML, Xia L, Dixon JB, Chen H, Srinivasan RS. Mechanotransduction activates canonical Wnt/β-catenin signaling to promote lymphatic vascular patterning and the development of lymphatic and lymphovenous valves. Genes Dev. 2016 June 15; 30(12): 1454-69. [Abstract] PMCID: PMC4926867
Pan Y, Yago T, Fu J, Herzog B, McDaniel JM, Padmaja Mehta-D’souza, Cai X, Ruan C, McEver RP, West C, Dai K, Chen H, Xia L. Podoplanin requires sialylated O-glycans for stable expression on lymphatic endothelial cells and for interaction with platelets. Blood. 2014 Dec 4;124(24):3656-65. [Abstract] PMCID: PMC4256915
Bergstrom K, Liu X, Zhao Y, Gao N, Wu Q, Song K, Cui Yi, Li Y, McDaniel JM, McGee S, Chen W, Huycke MM, Houchen CW, Zenewicz LA, West CM, Chen H, Braun J, Fu J*, Xia L. Defective intestinal mucin-type O-glycosylation causes spontaneous colitis-associated cancer in mice. Gastroenterology. 2016 July; 151(1):152-164.e11. [Abstract] PMCID: PMC5068133 *co-corresponding author
Astarita JL, Cremasco V, Fu J, Darnell MC, Peck JR, Nieves-Bonilla JM, Song K, Kondo Y, Woodruff MC, Gogineni A, Onder L, Ludewig B, Weimer RM, Carroll MC, Mooney DJ, Xia L, Turley SJ. The CLEC-2-podoplanin axis controls the contractility of fibroblastic reticular cells and lymph node microarchitecture. Nat Immunol. 2015 Jan;16(1):75-84. [Abstract] PMCID: PMC4270928
Herzog BH, Fu J*, Wilson SJ, Hess PR, Sen A, McDaniel JM, Pan Y, Sheng M, Yago T, Silasi-Mansat R, McGee S, May F, Nieswandt B, Morris AJ, Lupu F, Coughlin SR, McEver RP, Chen H, Kahn ML, Xia L. Podoplanin maintains high endothelial venule integrity by interacting with platelet CLEC-2. Nature. 2013 Oct 3;502(7469):105-9. [Abstract] PMCID: PMC3791160 *co-first author
Fu J, Wei B, Wen T, Johansson ME, Liu X, Bradford E, Thomsson KA, McGee S, Mansour L, Tong M, McDaniel JM, Sferra TJ, Turner J, Chen H, Hansson GC, Braun J, Xia L. Loss of intestinal core 1-derived O-glycans causes spontaneous colitis in mice. J Clin Invest. 2011 Apr;121(4):1657-66. [Abstract] PMCID: PMC3069788
Yago T, Fu J, McDaniel JM, Miner JJ, McEver RP, Xia L. Core 1-derived O-glycans are essential E-selectin ligands on neutrophils. Proc Natl Acad Sci U S A. 2010 May 18;107(20):9204-9. [Abstract] PMCID: PMC2889084
Fu J, Gerhardt H, McDaniel JM, Xia B, Liu X, Ivanciu L, Ny A, Hermans K, Silasi-Mansat R, McGee S, Nye E, Ju T, Ramirez MI, Carmeliet P, Cummings RD, Lupu F, Xia L. Endothelial O-glycan deficiency causes blood/lymphatic misconnections and consequent fatty liver disease in mice. J Clin Invest. 2008 Nov;118(11):3725-37. [Abstract] PMCID: PMC2567837
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