Guoqiang Gu, Ph.D.

Associate Professor

guoqiang.gu@vanderbilt.edu

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Faculty Appointments
Associate Professor of Cell and Developmental Biology
Education
Ph.D., Molecular Genetics, Columbia University, New York, New YorkM.S., Protein Biophysics, Chinese Academy of Sciences, Beijing, ChinaB.S., Biochemistry, Jilin University, Changchun, China
Office Address
2213 Garland Avenue, MRB4, Rm 9415
Nashville, TN 37232-8240
Research Description
INVESTIGATING PANCREATIC BETA CELL PRODUCTION AND FUNCTION

My laboratory studies the molecular and cellular mechanisms underlying beta cell production, function, and maintenance in the vertebrate pancreas. De-regulation of the above processes result in diabetes, which afflict over 5% of the world populations.

Utilizing mouse and chicken embryonic models, our studies focus on the following areas:

1) Technology development: A challenge of studying organogenesis in mammals is to follow specific cells in vivo. The available Cre-Lox-based technology allows for temporal and spatial cell marking and gene activity manipulation. The drawback of this technique is that all cells that express Cre will be labeled, which includes multiple cell types. We have engineered two inactive Cre fragments that can reconstitute Cre in cells that simultaneously express dual protein markers. This has enabled the identification of beta-cell progenitor cells and high-resolution genetic/epigenetic manipulations. This is particularly useful for examining how seemingly identical progenitor cells adopt different cell fate, either as pre-deterministic or stochastic model.

2) Novel mode of cell-cell communication for coordinated cellular differentiation: GAP junctions between cells not only allows for the exchange of small molecules, but also large peptides and nucleic acids. We are currently exploring whether miRNA-based mechanism coordinate endocrine cell differentiation through gap junctions, aided by RNASeq- and miRNAseq-based techniques.

3) Differentiation, survival, and function. With state-of-the-art technologies such as FACS-based cell sorting, RNAseq, and CHIPseq, we purify progenitor and functional cells to identify genetic networks that direct beta-cell differentiation and function. We have shown that the Myt1 family of transcription factors are particularly involved in protecting beta cell viability during insulin secretion. Interestingly, the effect of Myt factor appears to be mediated by controlling the expression of heat shock proteins. We are currently testing whether Myt factors directly regulate the expression of the heat shock factors.

4) Vesicular transportation in beta cells. It is generally believed that secretory vesicles were transported from deep within cells to underneath the plasma membrane along microtubules for their secretion. We have found, in collaboration with Dr. Kaverina, that beta cells do not utilize this common mechanism. Instead, vesicular free diffusion is sufficient to transport insulin vesicles from their site of production to the plasma membrane for their release. Microtubules, on the other hand, appear to inhibit insulin release by transporting vesicles away from the plasma membrane. We are currently investigating the mechanism for this negative regulation and testing whether microtubule targeting drugs can alleviate diabetes in mouse models.
Clinical Description
We study pancreatic beta cell development and function. One of our main interests is to examine the gene expression alteration when beta cells are subject to stress and dysfunction. We further determine whether such markers, such as miRNA, can be leaked into plasma as biomarkers.
Research Keywords
pancreatic development, diabetes, stem cells, microarray, RNAseq, notch signaling, combinatorial lineage tracing, gap junctions, microRNAs, vesicle transport and docking, microtubules, epigenetics, methylation.
Publications
Conrad E, Dai C, Spaeth J, Guo M, Cyphert HA, Scoville D, Carroll J, Yu WM, Goodrich LV, Harlan DM, Grove KL, Roberts CT, Powers AC, Gu G, Stein R. The MAFB transcription factor impacts islet a-cell function in rodents and represents a unique signature of primate islet ß-cells. Am. J. Physiol. Endocrinol. Metab [print-electronic]. 2016 Jan 1/1/2016; 310(1): E91-E102. PMID: 26554594, PMCID: PMC4675799, PII: ajpendo.00285.2015, DOI: 10.1152/ajpendo.00285.2015, ISSN: 1522-1555.

Gross S, Balderes D, Liu J, Asfaha S, Gu G, Wang TC, Sussel L. Nkx2.2 is expressed in a subset of enteroendocrine cells with expanded lineage potential. Am. J. Physiol. Gastrointest. Liver Physiol [print-electronic]. 2015 Dec 12/15/2015; 309(12): G975-87. PMID: 26492922, PMCID: PMC4683302, PII: ajpgi.00244.2015, DOI: 10.1152/ajpgi.00244.2015, ISSN: 1522-1547.

Zhu X, Hu R, Brissova M, Stein RW, Powers AC, Gu G, Kaverina I. Microtubules Negatively Regulate Insulin Secretion in Pancreatic ß Cells. Dev. Cell. 2015 Sep 9/28/2015; 34(6): 656-68. PMID: 26418295, PMCID: PMC4594944, PII: S1534-5807(15)00554-7, DOI: 10.1016/j.devcel.2015.08.020, ISSN: 1878-1551.

Kao DI, Lacko LA, Ding BS, Huang C, Phung K, Gu G, Rafii S, Stuhlmann H, Chen S. Endothelial cells control pancreatic cell fate at defined stages through EGFL7 signaling. Stem Cell Reports [print-electronic]. 2015 Feb 2/10/2015; 4(2): 181-9. PMID: 25601205, PMCID: PMC4325230, PII: S2213-6711(14)00385-3, DOI: 10.1016/j.stemcr.2014.12.008, ISSN: 2213-6711.

Chera S, Baronnier D, Ghila L, Cigliola V, Jensen JN, Gu G, Furuyama K, Thorel F, Gribble FM, Reimann F, Herrera PL. Diabetes recovery by age-dependent conversion of pancreatic d-cells into insulin producers. Nature [print-electronic]. 2014 Oct 10/23/2014; 514(7523): 503-7. PMID: 25141178, PMCID: PMC4209186, PII: nature13633, DOI: 10.1038/nature13633, ISSN: 1476-4687.

Yanger K, Knigin D, Zong Y, Maggs L, Gu G, Akiyama H, Pikarsky E, Stanger BZ. Adult hepatocytes are generated by self-duplication rather than stem cell differentiation. Cell Stem Cell [print-electronic]. 2014 Sep 9/4/2014; 15(3): 340-9. PMID: 25130492, PMCID: PMC4505916, PII: S1934-5909(14)00251-3, DOI: 10.1016/j.stem.2014.06.003, ISSN: 1875-9777.

Sancho R, Gruber R, Gu G, Behrens A. Loss of Fbw7 reprograms adult pancreatic ductal cells into a, d, and ß cells. Cell Stem Cell. 2014 Aug 8/7/2014; 15(2): 139-53. PMID: 25105579, PMCID: PMC4136739, PII: S1934-5909(14)00295-1, DOI: 10.1016/j.stem.2014.06.019, ISSN: 1875-9777.

Baeyens L, Lemper M, Leuckx G, De Groef S, Bonfanti P, Stangé G, Shemer R, Nord C, Scheel DW, Pan FC, Ahlgren U, Gu G, Stoffers DA, Dor Y, Ferrer J, Gradwohl G, Wright CV, Van de Casteele M, German MS, Bouwens L, Heimberg H. Transient cytokine treatment induces acinar cell reprogramming and regenerates functional beta cell mass in diabetic mice. Nat. Biotechnol [print-electronic]. 2014 Jan; 32(1): 76-83. PMID: 24240391, PMCID: PMC4096987, PII: nbt.2747, DOI: 10.1038/nbt.2747, ISSN: 1546-1696.

Arcidiacono B, Iiritano S, Chiefari E, Brunetti FS, Gu G, Foti DP, Brunetti A. Cooperation between HMGA1, PDX-1, and MafA is Essential for Glucose-Induced Insulin Transcription in Pancreatic Beta Cells. Front Endocrinol (Lausanne). 2014; 5: 237. PMID: 25628604, PMCID: PMC4292585, DOI: 10.3389/fendo.2014.00237, ISSN: 1664-2392.

Liu J, Willet SG, Bankaitis ED, Xu Y, Wright CV, Gu G. Non-parallel recombination limits Cre-LoxP-based reporters as precise indicators of conditional genetic manipulation. Genesis [print-electronic]. 2013 Jun; 51(6): 436-42. PMID: 23441020, PMCID: PMC3696028, DOI: 10.1002/dvg.22384, ISSN: 1526-968X.

Takuya Sugiyama, Cecil M. Benitez, Amar Ghodasara, Lucy Liu, Graeme W. McLean, Jonghyeob Lee, Timothy A. Blauwkamp, Roeland Nusse, Christopher V. E. Wright, Guoqiang Gu, and Seung K. Kima,. Reconstituting pancreas development from purified progenitor cells reveals genes essential for islet differentiation. 2013.

Maia AR, Zhu X, Miller P, Gu G, Maiato H, Kaverina I. Modulation of Golgi-associated microtubule nucleation throughout the cell cycle. Cytoskeleton (Hoboken) [print-electronic]. 2013 Jan; 70(1): 32-43. PMID: 23027431, PMCID: PMC3574797, DOI: 10.1002/cm.21079, ISSN: 1949-3592.

He W, Xie Q, Wang Y, Chen J, Zhao M, Davis LS, Breyer MD, Gu G, Hao CM. Generation of a tenascin-C-CreER2 knockin mouse line for conditional DNA recombination in renal medullary interstitial cells. PLoS ONE. 2013; 8(11): e79839. PMID: 24244568, PMCID: PMC3823583, PII: PONE-D-13-32413, DOI: 10.1371/journal.pone.0079839, ISSN: 1932-6203.

Ray KC, Bell KM, Yan J, Gu G, Chung CH, Washington MK, Means AL. Epithelial tissues have varying degrees of susceptibility to Kras(G12D)-initiated tumorigenesis in a mouse model. PLoS ONE. 2011; 6(2): e16786. PMID: 21311774, PMCID: PMC3032792, DOI: 10.1371/journal.pone.0016786, ISSN: 1932-6203.

Zhao A, Ohara-Imaizumi M, Brissova M, Benninger RK, Xu Y, Hao Y, Abramowitz J, Boulay G, Powers AC, Piston D, Jiang M, Nagamatsu S, Birnbaumer L, Gu G. Gao represses insulin secretion by reducing vesicular docking in pancreatic beta-cells. Diabetes [print-electronic]. 2010 Oct; 59(10): 2522-9. PMID: 20622165, PMCID: PMC3279551, PII: db09-1719, DOI: 10.2337/db09-1719, ISSN: 1939-327X.

Wang S, Yan J, Anderson DA, Xu Y, Kanal MC, Cao Z, Wright CV, Gu G. Neurog3 gene dosage regulates allocation of endocrine and exocrine cell fates in the developing mouse pancreas. Dev. Biol [print-electronic]. 2010 Mar 3/1/2010; 339(1): 26-37. PMID: 20025861, PMCID: PMC2824035, PII: S0012-1606(09)01398-0, DOI: 10.1016/j.ydbio.2009.12.009, ISSN: 1095-564X.

Wang S, Jensen JN, Seymour PA, Hsu W, Dor Y, Sander M, Magnuson MA, Serup P, Gu G. Sustained Neurog3 expression in hormone-expressing islet cells is required for endocrine maturation and function. Proc. Natl. Acad. Sci. U.S.A [print-electronic]. 2009 Jun 6/16/2009; 106(24): 9715-20. PMID: 19487660, PMCID: PMC2701002, PII: 0904247106, DOI: 10.1073/pnas.0904247106, ISSN: 1091-6490.

Artner I, Hang Y, Guo M, Gu G, Stein R. MafA is a dedicated activator of the insulin gene in vivo. J. Endocrinol [print-electronic]. 2008 Aug; 198(2): 271-9. PMID: 18515495, PMCID: PMC3787904, PII: JOE-08-0063, DOI: 10.1677/JOE-08-0063, ISSN: 1479-6805.

Means AL, Xu Y, Zhao A, Ray KC, Gu G. A CK19(CreERT) knockin mouse line allows for conditional DNA recombination in epithelial cells in multiple endodermal organs. Genesis. 2008 Jun; 46(6): 318-23. PMID: 18543299, PMCID: PMC3735352, DOI: 10.1002/dvg.20397, ISSN: 1526-968X.

Wang S, Hecksher-Sorensen J, Xu Y, Zhao A, Dor Y, Rosenberg L, Serup P, Gu G. Myt1 and Ngn3 form a feed-forward expression loop to promote endocrine islet cell differentiation. Dev. Biol [print-electronic]. 2008 May 5/15/2008; 317(2): 531-40. PMID: 18394599, PMCID: PMC2423199, PII: S0012-1606(08)00179-6, DOI: 10.1016/j.ydbio.2008.02.052, ISSN: 1095-564X.

Wang S, Zhang J, Zhao A, Hipkens S, Magnuson MA, Gu G. Loss of Myt1 function partially compromises endocrine islet cell differentiation and pancreatic physiological function in the mouse. Mech. Dev [print-electronic]. 2007 Nov; 124(11-12): 898-910. PMID: 17928203, PMCID: PMC2141686, PII: S0925-4773(07)00147-5, DOI: 10.1016/j.mod.2007.08.004, ISSN: 0925-4773.

Gu G, Yuan J, Wills M, Kasper S. Prostate cancer cells with stem cell characteristics reconstitute the original human tumor in vivo. Cancer Res. 2007 May 5/15/2007; 67(10): 4807-15. PMID: 17510410, PII: 67/10/4807, DOI: 10.1158/0008-5472.CAN-06-4608, ISSN: 0008-5472.

Johansson KA, Dursun U, Jordan N, Gu G, Beermann F, Gradwohl G, Grapin-Botton A. Temporal control of neurogenin3 activity in pancreas progenitors reveals competence windows for the generation of different endocrine cell types. Dev. Cell. 2007 Mar; 12(3): 457-65. PMID: 17336910, PII: S1534-5807(07)00061-5, DOI: 10.1016/j.devcel.2007.02.010, ISSN: 1534-5807.

Xu Y, Xu G, Liu B, Gu G. Cre reconstitution allows for DNA recombination selectively in dual-marker-expressing cells in transgenic mice. Nucleic Acids Res [print-electronic]. 2007; 35(19): e126. PMID: 17893102, PMCID: PMC2095822, PII: gkm559, DOI: 10.1093/nar/gkm559, ISSN: 1362-4962.

Xu Y, Wang S, Zhang J, Zhao A, Stanger BZ, Gu G. The fringe molecules induce endocrine differentiation in embryonic endoderm by activating cMyt1/cMyt3. Dev. Biol [print-electronic]. 2006 Sep 9/15/2006; 297(2): 340-9. PMID: 16920096, PII: S0012-1606(06)00753-6, DOI: 10.1016/j.ydbio.2006.04.456, ISSN: 0012-1606.

Nikolova G, Jabs N, Konstantinova I, Domogatskaya A, Tryggvason K, Sorokin L, Fässler R, Gu G, Gerber HP, Ferrara N, Melton DA, Lammert E. The vascular basement membrane: a niche for insulin gene expression and Beta cell proliferation. Dev. Cell. 2006 Mar; 10(3): 397-405. PMID: 16516842, PII: S1534-5807(06)00061-X, DOI: 10.1016/j.devcel.2006.01.015, ISSN: 1534-5807.

Emtage L, Gu G, Hartwieg E, Chalfie M. Extracellular proteins organize the mechanosensory channel complex in C. elegans touch receptor neurons. Neuron. 2004 Dec 12/2/2004; 44(5): 795-807. PMID: 15572111, PII: S0896627304007251, DOI: 10.1016/j.neuron.2004.11.010, ISSN: 0896-6273.

Gu G, Wells JM, Dombkowski D, Preffer F, Aronow B, Melton DA. Global expression analysis of gene regulatory pathways during endocrine pancreatic development. Development [print-electronic]. 2004 Jan; 131(1): 165-79. PMID: 14660441, PII: dev.00921, DOI: 10.1242/dev.00921, ISSN: 0950-1991.

Gu G, Brown JR, Melton DA. Direct lineage tracing reveals the ontogeny of pancreatic cell fates during mouse embryogenesis. Mech. Dev. 2003 Jan; 120(1): 35-43. PMID: 12490294, PII: S0925477302003301, ISSN: 0925-4773.

Lammert E, Gu G, McLaughlin M, Brown D, Brekken R, Murtaugh LC, Gerber HP, Ferrara N, Melton DA. Role of VEGF-A in vascularization of pancreatic islets. Curr. Biol. 2003; 13((June 17)): 1070-4.

Gu G, Reyes PE, Golden GT, Woltjer RL, Hulette C, Montine TJ, Zhang J. Mitochondrial DNA deletions/rearrangements in parkinson disease and related neurodegenerative disorders. J. Neuropathol. Exp. Neurol. 2002 Jul; 61(7): 634-9. PMID: 12125742, ISSN: 0022-3069.

Gu G, Dubauskaite J, Melton DA. Direct evidence for the pancreatic lineage: NGN3+ cells are islet progenitors and are distinct from duct progenitors. Development. 2002 May; 129(10): 2447-57. PMID: 11973276, ISSN: 0950-1991.

Jiang P, Song J, Gu G, Slonimsky E, Li E, Rosenthal N. Deletion of the MLC1f/3f downstream enhancer results in precocious MLC expression and mesoderm ablation. Dev. Biol. 2002; 243((Mar. 15)): 281-93.

Hall DH, Gu G, García-Añoveros J, Gong L, Chalfie M, Driscoll M. Neuropathology of degenerative cell death in Caenorhabditis elegans. J. Neurosci. 1997 Feb 2/1/1997; 17(3): 1033-45. PMID: 8994058, ISSN: 0270-6474.

Gu G, Caldwell GA, Chalfie M. Genetic interactions affecting touch sensitivity in Caenorhabditis elegans. Proc. Natl. Acad. Sci. U.S.A. 1996 Jun 6/25/1996; 93(13): 6577-82. PMID: 8692859, PMCID: PMC39067, ISSN: 0027-8424.

Du H, Gu G, William CM, Chalfie M. Extracellular proteins needed for C. elegans mechanosensation. Neuron. 1996 Jan; 16(1): 183-94. PMID: 8562083, PII: S0896-6273(00)80035-5, ISSN: 0896-6273.

Huang M, Gu G, Ferguson EL, Chalfie M. A stomatin-like protein necessary for mechanosensation in C. elegans. Nature. 1995 Nov 11/16/1995; 378(6554): 292-5. PMID: 7477350, DOI: 10.1038/378292a0, ISSN: 0028-0836.

Available Postdoctoral Position Details
Posted: 9/22/2014
One postdoctoral position available for studying endocrine islet cell development. Available projects includes: 1) characterizing genes expression during mouse pancreas development; 2) generating transgenic and knockout mice to evaluate gene function for endocrine islet development, beta cell maturation, and functional maintenance; 3) using chicken embryos to screen for genes required for endocrine cell differentiation, and 4) using cell lineage tracing methods to understand islet homeostasis and adult pancreatic stem/progenitor cells.