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One of the cell biology enigmas is how cells achieve asymmetry to facilitate their directional migration, secretion, asymmetric division, and responding to extrinsic signals. We are interested in mammalian epithelial cell polarity mechanisms that are related to developmental and pathological processes, such as the morphogenesis and oncogenesis of the gastrointestinal epithelium, the glucose-directed insulin granule vesicular exocytosis in healthy and diabetic beta-cells. We derive and characterize genetically engineered mouse models, apply classic biochemistry and modern cell biology tools to explore the molecular mechanisms underlying the interfaces of cell polarity, development, stem cell and cancer.
How is apical-basal protein trafficking regulated during epithelial morphogenesis?
The apical-basal polarization of mammalian gut epithelium takes place within a short period of time during fetal morphogenesis. In mice, the midgut endoderm initiates a dramatic morphological transition around embryonic day 14.5, polarizing into a single-layered columnar intestinal epithelium. Polarized enterocytes, one of the major intestinal cell types, form a continuous epithelial layer along the intestinal tract and serve as a permeable barrier between the luminal contents and blood supply. Individual enterocyte forms structurally and functionally distinct plasma membrane domains. The apical domain faces the lumen, and contains essential enzymes and transporters that facilitate the uptake of nutrients. The basolateral domain faces neighboring epithelial cells and the extracellular matrix, and contains extracellular matrix receptors, ion channels and solute transporters that facilitate the transduction of nutrients into the blood vessels. We are interested in two long-term questions: (1) what are the initial intrinsic and extrinsic cues for polarity induction? (2) What is the molecular network that executes and maintains the polarity? We are currently investigating the role of a cascade of small GTPases in apical and basolateral protein trafficking during intestinal morphogenesis, and exploring their contribution to a polarity defect called Congenital Microvillus Inclusion Diseases.
How is asymmetric cell division regulated in somatic self renewal stem cells?
The postnatal intestinal epithelium contains a stem cell niche, the crypt, and a villus compartment. The latter is constantly replenished by the cryptic stem cells throughout the life. This small group of stem cells migrates up along the crypt-villus axis, after transit-amplification, giving rise to postmitotic cells that differentiate into four functionally different mature cell types. We are interested in the molecular mechanisms that control the asymmetric division and differentiation of these stem cells. Using genetic lineage tracing, we are now able to mark these stem cells and track their descendents, and investigate the developmental consequences of mutant stem cells harboring targeted mutations in key polarity genes.
Polarity pathways in epithelial cancer
Loss of epithelial polarity is a key diagnostic feature of most adenocarcinoma (malignant tumor that starts in epithelial tissue). The involvement of polarity genes in human intestinal tumors has been demonstrated by the finding that germ-line mutations of LKB1 (or Serine-threonine kinase 11, a basally located polarity regulator) underlie most cases of Peutz-Jeghers syndrome (PJS). Patients with PJS develop intestinal polyps and carcinomas. Tumor suppressor adenomatous polyposis coli (APC) associates with a variety of polarity regulatory components and is regulated spatially by Cdc42/Par-aPKC to control cell polarization. Using several established colon cancer mouse models and biochemical approaches, we are investigating the genetic and biochemical relationship of a central polarity network, and its contribution to intestinal tumor formation.
How is polarity cue coupled to insulin exocytotic machinery in beta-cells?
The pancreatic beta-cells of diabetic patients are incompetent to secrete insulin in response to glucose stimulations. Although the metabolism of glucose plays a critical role in mobilization and exocytosis of insulin granules, the molecular mechanisms of how the vesicular transport, movement, membrane-targeting, fusion, docking, recycling are controlled are not well-defined. This is an exciting research direction, and we are currently working on a few pilot experiments to try to initiate the project.
B.S. in Medicine, Soochow University, China, 1997.
M.S. in Cancer Biology, Fudan University, China, 2000.
Ph.D. in Cell and Developmental Biology, Vanderbilt University, 2004.
Das S, Yu S, Sakamori R, Stypulkowski E, Gao N. Wntless in Wnt secretion: molecular, cellular and genetic aspects. Front Biol (2012); 7(6):587-593.
Sakamori R, Das S, Yu SY, Feng SS, Stypulkowski E, Guan YZ, Douard V, Tang WX, Ferraris RP, Harada A, Brakebusch C, Guo W, Gao N. Cdc42 and Rab8 are critical for intestinal stem cell division, survival, and differentiation in mice. Journal of Clinical Investigation (2012); 122(3):1052-1065.
Gao N, Davuluri G, Gong W, Seiler C, Lorent K, Furth EE, Kaestner KH, Pack M. The nuclear pore complex protein Elys is required for genome stability in mouse intestinal epithelial progenitor cells. Gastroenterology (2011); 140(5):1547-1555.
Gao N, Le Lay J, Qin W, Doliba N, Schug J, Fox AJ, Smirnova O, Matschinsky FM, Kaestner KH. Foxa1 and Foxa2 maintain the metabolic and secretory features of mature β-cell. Molecular Endocrinology (2010); 24(8):1594-604.
Gao N and Kaestner KH. Cdx2 regulates endo-lysosomal function and epithelial cell polarity. Genes & Development (2010); 24(12):1295-305. (COVER).
Gao N, White P, Kaestner KH. Establishment of Intestinal Identity and Epithelial-Mesenchymal Signalling by Cdx2. Developmental Cell (2009); 16(4): 588-599.
Gao N, Le Lay J, Vatamaniuk MZ, Rieck S, Friedman JR and Kaestner KH. Dynamic regulation of Pdx1 enhancers by Foxa1 and Foxa2 is essential for pancreas development. Genes & Development (2008); 22:3435-3448.
Gupta RK*, Gao N*, Gorski RK, White P, Hardy OT, Rafiq K, Brestelli JE, Chen G, Stoeckert CJ Jr, Kaestner KH. Expansion of adult beta-cell mass in response to increased metabolic demand is dependent on HNF-4alpha. Genes & Development (2007); 21(7):756-69. (* Co-first authors)
Hinoi E, Gao N, Jung DY, Yadav V, Yoshizawa T, Myers Jr. MG, Streamson C. Chua Jr., Kim JK, Kaestner KH, and Karsenty G. The sympathetic tone mediates leptin’s inhibition of insulin secretion by modulating osteocalcin bioactivity.The Journal of Cell Biology (2008); 183(7):1235-42.
Gao N, White P, Doliba N, Golson M, Matschinsky FM, Kaestner KH. Foxa2 controls vesicle docking and insulin secretion in mature beta cells. Cell Metabolism (2007); 6(4):267-79.
Gao N*, Ishii K*, Mirosevich J, Kuwajima S, Oppenheimer SR, Roberts R, Jiang M, Xiuping Yu, Sheppell S, Caprioli RM, Stoffel M, Hayward SW, Matusik RJ. Forkhead Box A1 regulates prostatic ductal morphogenesis and promotes epithelial cell maturation. Development (2005); 132: 3431-3443. (*Co-first authors).
Chen MH, Gao N, Kawakami T, Chuang PT. Mice deficient in the Fused homolog do not exibit phenotypes indicative of perturbed hedgehog signaling during embryonic development. Molecular and Cellular Biology (2005); 25(16):7042-53.
Gao N, Zhang J, Rao MA, Case TC, Mirosevich J, Wang Y, Jin R, Gupta A, Rennie PS, Matusik RJ. The role of hepatocyte nuclear factor-3 alpha (Forkhead Box A1) and androgen receptor in transcriptional regulation of prostatic genes. Molecular Endocrinology (2003); 17(8):1484-1507.