The pancreas is essential for normal digestion and maintenance of blood sugar levels.  We study the role of genes and signaling pathways involved in the development and function of specific cell types within the pancreas.  The HNF6 transcription factor is expressed in all pancreas cells early in embryonic development, but is "turned off" in islet cells just before birth in the mouse.  We developed mice in which HNF6 is over-expressed or can be inactivated conditionally.  These studies reveal that HNF6 is essential to generate the appropriate number of endocrine progenitor cells, but that it must get "turned off" in order for the insulin-producing cells to function properly.  Current studies are examining how HNF6 interacts with other factors in the embryonic pancreas to regulate endocrine differentiation.  Our studies also revealed that HNF6 is essential for normal growth and branching of the pancreatic ductal epithelium.  In the absence of HNF6, pancreatic duct differentiation is impaired and the mice develop pancreatitis.

A second project in the lab examines the role of CTGF, a secreted factor known to modulate growth factor signaling and affect cell proliferation and migration in other organ systems.  We found that loss of CTGF results in decreased embryonic islet beta cell proliferation and defective islet formation.  We are using conditional gene inactivation and over-expression strategies to determine how CTGF affects islet development and function during embryogenesis and after transplantation.

Finally, the FoxM1 transcription factor is highly expressed in proliferating cells and is essential for normal cell division.  We generated mice specifically lacking FoxM1 in the pancreas.  In these mice, the number of insulin-producing cells fails to increase with body mass, resulting in diabetes.  Significantly, we found that FoxM1 is required downstream of all proliferative stimuli in the insulin-producing beta cells.  For example, the number of beta cells expands via mitosis when animals are fed a high fat diet, or during pregnancy.  In FoxM1 mutants, this increase in mitosis does not occur and the animals become diabetic.  Our current studies are aimed at characterizing the signaling pathways that activate FoxM1 expression and activity as well as identifying target genes of FoxM1 in the insulin-producing cells.

Publications

Featured publications

  1. An assay for small scale screening of candidate β cell proliferative factors using intact islets. Mosser RE, Gannon M (2013) Biotechniques 55(6): 310-2
    › Primary publication · 24344680 (PubMed) · PMC4764137 (PubMed Central)
  2. High Fat Diet Regulation of β-Cell Proliferation and β-Cell Mass. Golson ML, Misfeldt AA, Kopsombut UG, Petersen CP, Gannon M (2010) Open Endocrinol J
    › Primary publication · 24339840 (PubMed) · PMC3856766 (PubMed Central)
  3. Connective tissue growth factor (CTGF/CCN2) negatively regulates BMP-2 induced osteoblast differentiation and signaling. Mundy C, Gannon M, Popoff SN (2014) J Cell Physiol 229(5): 672-81
    › Primary publication · 24127409 (PubMed) · PMC3946942 (PubMed Central)
  4. Advancements and challenges in generating accurate animal models of gestational diabetes mellitus. Pasek RC, Gannon M (2013) Am J Physiol Endocrinol Metab 305(11): E1327-38
    › Primary publication · 24085033 (PubMed) · PMC4073988 (PubMed Central)
  5. The skeletal site-specific role of connective tissue growth factor in prenatal osteogenesis. Lambi AG, Pankratz TL, Mundy C, Gannon M, Barbe MF, Richtsmeier JT, Popoff SN (2012) Dev Dyn 241(12): 1944-59
    › Primary publication · 23073844 (PubMed) · PMC3752831 (PubMed Central)
  6. Inactivation of the dual Bmp/Wnt inhibitor Sostdc1 enhances pancreatic islet function. Henley KD, Gooding KA, Economides AN, Gannon M (2012) Am J Physiol Endocrinol Metab 303(6): E752-61
    › Primary publication · 22829579 (PubMed) · PMC3468431 (PubMed Central)
  7. Differential regulation of embryonic and adult β cell replication. Gunasekaran U, Hudgens CW, Wright BT, Maulis MF, Gannon M (2012) Cell Cycle 11(13): 2431-42
    › Primary publication · 22659844 (PubMed) · PMC3404874 (PubMed Central)
  8. Tamoxifen-Induced Cre-loxP Recombination Is Prolonged in Pancreatic Islets of Adult Mice. Reinert RB, Kantz J, Misfeldt AA, Poffenberger G, Gannon M, Brissova M, Powers AC (2012) PLoS One 7(3): e33529
    › Primary publication · 22470452 (PubMed) · PMC3314663 (PubMed Central)
  9. Connective tissue growth factor acts within both endothelial cells and beta cells to promote proliferation of developing beta cells. Guney MA, Petersen CP, Boustani A, Duncan MR, Gunasekaran U, Menon R, Warfield C, Grotendorst GR, Means AL, Economides AN, Gannon M (2011) Proc Natl Acad Sci U S A 108(37): 15242-7
    › Primary publication · 21876171 (PubMed) · PMC3174622 (PubMed Central)
  10. Type 2 diabetes and the aging pancreatic beta cell. Gunasekaran U, Gannon M (2011) Aging (Albany NY) 3(6): 565-75
    › Primary publication · 21765202 (PubMed) · PMC3164365 (PubMed Central)