Vanderbilt University School of Medicine

Gu, Guoqiang , Ph.D.
Associate Professor of Cell and Developmental Biology

Lab Url: http://www.guoqianggulab.org/Welcome.html

Phone Number: 936-3634

Email Address:guoqiang.gu@vanderbilt.edu

Gu, Guoqiang's picture

Office Address   Mailing Address

2213 Garland Avenue, MRB4, Rm 9415

2213 Garland Avenue, MRB4, Rm 9415 37232-8240


Research Keywords
pancreatic development, diabetes, stem cells, microarray, RNAseq, notch signaling, combinatorial lineage tracing, gap junctions, microRNAs, vesicle transport and docking, microtubules.,Developmental biology,Diabetes,Gene regulation,Genetics,Knockout,Mouse,Physiology,Stem cells

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

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.



Publications
Baeyens, L, Lemper, M, Leuckx, G, De Groef, S, Bonfanti, P, Stang??, 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, 32(1), 76-83, 2014.

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. PNAS, , , 2013.

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, 51(6), 436-42, 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), 70(1), 32-43, 2013.

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, 6(2), e16786, 2011. PMCID:3032792

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, 339(1), 26-37, 2010. PMCID:2824035

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. GI?o represses insulin secretion by reducing vesicular docking in pancreatic beta-cells. Diabetes, 59(10), 2522-9, 2010. PMCID:3032792

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, 106(24), 9715-20, 2009. PMCID:2701002

Artner, I, Hang, Y, Guo, M, Gu, G, Stein, R. MafA is a dedicated activator of the insulin gene in vivo. J Endocrinol, 198(2), 271-9, 2008.

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, 46(6), 318-23, 2008.

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, 317(2), 531-40, 2008. PMCID:2423199

Gu, G, Yuan, J, Wills, M, Kasper, S. Prostate cancer cells with stem cell characteristics reconstitute the original human tumor in vivo. Cancer Res, 67(10), 4807-15, 2007.

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, 12(3), 457-65, 2007.

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, 124(11-12), 898-910, 2007. PMCID:2141686

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, 35(19), e126, 2007. PMCID:2095822

Nikolova, G, Jabs, N, Konstantinova, I, Domogatskaya, A, Tryggvason, K, Sorokin, L, F??ssler, 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, 10(3), 397-405, 2006.

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, 297(2), 340-9, 2006.

Emtage, L, Gu, G, Hartwieg, E, Chalfie, M. Extracellular proteins organize the mechanosensory channel complex in C. elegans touch receptor neurons. Neuron, 44(5), 795-807, 2004.

Gu, G, Wells, JM, Dombkowski, D, Preffer, F, Aronow, B, Melton, DA. Global expression analysis of gene regulatory pathways during endocrine pancreatic development. Development, 131(1), 165-79, 2004.

Gu, G, Brown, JR, Melton, DA. Direct lineage tracing reveals the ontogeny of pancreatic cell fates during mouse embryogenesis. Mech Dev, 120(1), 35-43, 2003.

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., 13(June 17), 1070-1074, 2003.

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

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, 61(7), 634-9, 2002.

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., 243(Mar. 15), 281-293, 2002.

Hall, DH, Gu, G, Garc?-a-A??overos, J, Gong, L, Chalfie, M, Driscoll, M. Neuropathology of degenerative cell death in Caenorhabditis elegans. J Neurosci, 17(3), 1033-45, 1997.

Du, H, Gu, G, William, CM, Chalfie, M. Extracellular proteins needed for C. elegans mechanosensation. Neuron, 16(1), 183-94, 1996.

Gu, G, Caldwell, GA, Chalfie, M. Genetic interactions affecting touch sensitivity in Caenorhabditis elegans. Proc Natl Acad Sci U S A, 93(13), 6577-82, 1996. PMCID:39067

Huang, M, Gu, G, Ferguson, EL, Chalfie, M. A stomatin-like protein necessary for mechanosensation in C. elegans. Nature, 378(6554), 292-5, 1995.


Postdoctoral Position Available
Yes

Postdoctoral Position Details
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.

Updated Date
02/03/2014



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