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

The vertebrate pancreas includes exocrine and endocrine tissues that are responsible for digesting food and regulating sugar metabolism, respectively. Several diseases associate with the pancreas, including pancreatitis, diabetes, and pancreatic cancer, amongst which diabetes is the most prevalent that inflicts more than 27 million individuals in the United States.

We investigate the cellular and molecular mechanisms underlying islet cell differentiation and function, which include multiple endocrine cell types that secrete insulin (beta cells), glucagon (alpha cells), somatostatin (delta cells), and pancreatic polypeptide (PP cells), respectively. Our basic strategy is to first unambiguously identify progenitors of each specific cell type, then examine the molecular networks and cellular interactions for their development and function. Our studies focus on the following areas:

1) Technology development: A challenge of studying development and organogenesis in mammals is our inability to follow specific cells during their development to understand thwir specification and function. The Cre-Lox-based technology allows for temporal and spatial cell marking and gene activity manipulation, with a drawback of marking all cells that express Cre that includes multiple cell types. We have engineered two inactive Cre fragments that can reconstitute Cre in cells that simultaneously express dual protein markers. This enabled the identification of beta-cell progenitor cells and high-resolution analysis of the genetic/epigenetic programs that direct the production of functional beta cells. It also allows us to examine how seemingly identical progenitor cells adopt different cell fate, either as pre-deterministic or stochastic model. In the former possibility, progenitor may have differential gene expression and differentiation potentials. In the later model, progenitor cells are identical, yet stochastic transcription of certain factors could bias progenitors to specific cell fate.
2) Novel mode of cell-cell communication for coordinated cellular differentiation: Notch-mediated cell-cell interactions were known to select a specific set of pancreatic cells as endocrine progenitors by activating the expression of Ngn3. Yet Notch signaling alone cannot account for the coordinated differentiation of neighboring cells adopt islet cell fate at same time windows. We have shown that gap junction-mediated information can control this coordinated differentiation. 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 intermediate cell populations that have defined function and examine the genetic networks that direct cell differentiation and function. These studies avoid complications caused by unwanted cell types in tissue samples. We have identified several previously unidentified gene circuits that might participate endocrine differentiation and their role in islet production are being examined. We also identify factors that maintain beta cell survival during their function and stress, such as the Myt1 family of transcription factors. Lastly, we investigate how cellular structures, such as microtubules, direct beta cell function, in insulin vesicular transport and secretion. We are currently working on a hypothesis that microtubules in pancreatic beta cells act as a storage structure to fine-tune insulin secretion.


Research Keywords
pancreatic development, diabetes, stem cells, microarray, RNAseq, notch signaling, combinatorial lineage tracing, gap junctions, microRNAs, vesicle transport and docking, microtubules.
Publications
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.

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.