- Overview
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Diabetes mellitus results from dysfunction, damage or loss or of pancreatic ß-cells. These cells reside in small endocrine clusters, called the islets of Langerhans, which are interspersed throughout the pancreas and secrete the hormones insulin and glucagon in response to changes in blood glucose. In order to ameliorate and eventually cure both forms of diabetes, ß-cells will need to be functionally restored, regenerated, or replaced. Islet and pancreas transplantation have demonstrated the promise of ß-cell replacement, but a short supply of transplantable tissue limits the applicability of these approaches in broadly curing diabetes mellitus.
Our group is interested in understanding the mechanisms that regulate the formation of islet ß-cells from pancreatic stem or progenitor cells during solid organ formation. We focus on the gene regulatory networks at play in the progenitor cells and how these networks change during differentiation to mature endocrine cells and in the long-term maintenance of the ß-cell.
We believe that a greater understanding of these genetic mechanisms and pathways will refine cell-based approaches for preventing and reversing the ß-cell deterioration and loss that occur with diabetes.
- Publications
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HumanIslets: An integrated platform for human islet data access and analysis
bioRxiv
DOI: 10.1101/2024.06.19.599613
2024PDX1+ cell budding morphogenesis in a stem cell-derived islet spheroid system
Nature Communications
DOI: 10.1038/s41467-024-50109-2
2024An INSULIN and IAPP dual reporter enables tracking of functional maturation of stem cell-derived insulin producing cells
Molecular Metabolism
DOI: 10.1016/j.molmet.2024.102017
2024NPAS4 is an allostatic regulator of POMC neuronal activity during diet-induced obesity
bioRxiv
DOI: 10.1101/2024.01.12.574247
2024Characterizing the effects of Dechlorane Plus on ß-cells: a comparative study across models and species
Islets
DOI: 10.1080/19382014.2024.2361996
2024Single cell glucose-stimulated insulin secretion assay using nanowell-in-microwell plates
Lab on a Chip
DOI: 10.1039/d4lc00413b
2024Proteomic predictors of individualized nutrient-specific insulin secretion in health and disease
Cell Metabolism
DOI: 10.1016/j.cmet.2024.06.001
2024Novel time-resolved reporter mouse reveals spatial and transcriptional heterogeneity during alpha cell differentiation
Diabetologia
Himuro, M. and Wakabayashi, Y. and Taguchi, T. and Katahira, T. and Suzuki, L. and Iida, H. and Ogihara, T. and Nishida, Y. and Sasaki, S. and Lynn, F.C. and Hiraoka, Y. and Oshima, S. and Okamoto, R. and Fujitani, Y. and Watada, H. and Miyatsuka, T.
DOI: 10.1007/s00125-023-06028-w
2024Methylation of histone H3 lysine 4 is required for maintenance of beta cell function in adult mice
Diabetologia
Ben Vanderkruk and Nina Maeshima and Daniel J. Pasula and Meilin An and Cassandra L. McDonald and Priya Suresh and Dan S. Luciani and Francis C. Lynn and Brad G. Hoffman
DOI: 10.1007/s00125-023-05896-6
06/2023Tracking insulin- and glucagon-expressing bihormonal cells during differentiation using an INSULIN and GLUCAGON double reporter human embryonic stem cell line
bioRxiv
Mar, S. and Filatov, E. and Nian, C. and Sasaki, S. and Zhang, D. and Lynn, F.C.
DOI: 10.1101/2023.04.19.537542
2023Retraction Note: Calcium-dependent transcriptional changes in human pancreatic islet cells reveal functional diversity in islet cell subtypes (Diabetologia, (2022), 65, 9, (1519-1533), 10.1007/s00125-022-05718-1)
Diabetologia
Yoon, J.S. and Sasaki, S. and Velghe, J. and Lee, M.Y.Y. and Winata, H. and Nian, C. and Lynn, F.C.
DOI: 10.1007/s00125-023-05983-8
2023In silico discovery of small molecules for efficient stem cell differentiation into definitive endoderm
Stem Cell Reports
Novakovsky, G. and Sasaki, S. and Fornes, O. and Omur, M.E. and Huang, H. and Bayly, C.L. and Zhang, D. and Lim, N. and Cherkasov, A. and Pavlidis, P. and Mostafavi, S. and Lynn, F.C. and Wasserman, W.W.
DOI: 10.1016/j.stemcr.2023.01.008
2023Calcium-dependent transcriptional profiles of human pancreatic islet cells reveal functional diversity in islet subpopulations
bioRxiv
Yoon, J.S. and Sasaki, S. and Velghe, J. and Zosel, K. and Lee, M.Y.Y. and Winata, H. and Nian, C. and Lynn, F.C.
DOI: 10.1101/2023.09.08.556709
2023Truncated CD19 as a selection marker for the isolation of stem cell derived ß-cells
bioRxiv
Huang, L.T. and Zhang, D. and Nian, C. and Lynn, F.C.
DOI: 10.1101/2023.04.05.535733
2023Islet amyloid polypeptide does not suppress pancreatic cancer
Molecular metabolism
Taylor, A.J. and Panzhinskiy, E. and Orban, P.C. and Lynn, F.C. and Schaeffer, D.F. and Johnson, J.D. and Kopp, J.L. and Verchere, C.B.
DOI: 10.1016/j.molmet.2023.101667
2023Human A2-CAR T Cells Reject HLA-A2+Human Islets Transplanted into Mice Without Inducing Graft-versus-host Disease
Transplantation
Ellis, C.E. and Mojibian, M. and Ida, S. and Fung, V.C.W. and Skovs?, S?. and McIver, E. and O{'}Dwyer, S. and Webber, T.D. and Braam, M.J.S. and Saber, N. and Sasaki, S. and Lynn, F.C. and Kieffer, T.J. and Levings, M.K.
DOI: 10.1097/TP.0000000000004709
2023Type 2 diabetes susceptibility gene GRK5 regulates physiological pancreatic ß-cell proliferation via phosphorylation of HDAC5
iScience
Sasaki, S. and Nian, C. and Xu, E.E. and Pasula, D.J. and Winata, H. and Grover, S. and Luciani, D.S. and Lynn, F.C.
DOI: 10.1016/j.isci.2023.107311
2023Spatial and transcriptional heterogeneity of pancreatic beta cell neogenesis revealed by a time-resolved reporter system
Diabetologia
Shugo Sasaki and Michelle Y. Y. Lee and Yuka Wakabayashi and Luka Suzuki and Helena Winata and Miwa Himuro and Taka-aki Matsuoka and Iichiro Shimomura and Hirotaka Watada and Francis C. Lynn and Takeshi Miyatsuka
DOI: 10.1007/s00125-022-05662-0
05/2022Dynamic Ins2 Gene Activity Defines ß-Cell Maturity States
Diabetes
Chu, C.M.J. and Modi, H. and Ellis, C. and Krentz, N.A.J. and Skovs?, S. and Zhao, Y.B. and Cen, H. and Noursadeghi, N. and Panzhinskiy, E. and Hu, X. and Dionne, D.A. and Xia, Y.H. and Xuan, S. and Huising, M.O. and Kieffer, T.J. and Lynn, F.C. and Johnson, J.D.
DOI: 10.2337/db21-1065
2022Type 2 diabetes susceptibility gene GRK5 regulates physiological pancreatic ß-cell proliferation via phosphorylation of HDAC5 in mice
bioRxiv
Sasaki, S. and Nian, C. and Xu, E.E. and Pasula, D.J. and Winata, H. and Grover, S. and Luciani, D.S. and Lynn, F.C.
DOI: 10.1101/2022.12.23.521810
2022A versatile fluorescence-quenched substrate for quantitative measurement of glucocerebrosidase activity within live cells
Proceedings of the National Academy of Sciences of the United States of America
Deen, M.C. and Zhu, Y. and Gros, C. and Na, N. and Gilormini, P.-A. and Shen, D.L. and Bhosale, S. and Anastasi, N. and Wang, R. and Shan, X. and Harde, E. and Jagasia, R. and Lynn, F.C. and Vocadlo, D.J.
DOI: 10.1073/pnas.2200553119
2022Human JAK1 gain of function causes dysregulated myelopoeisis and severe allergic inflammation
JCI Insight
Biggs, C.M. and Cordeiro-Santanach, A. and Prykhozhij, S.V. and Deveau, A.P. and Lin, Y. and Del Bel, K.L. and Orben, F. and Ragotte, R.J. and Saferali, A. and Mostafavi, S. and Dinh, L. and Dai, D. and Weinacht, K.G. and Dobbs, K. and de Bruin, L.O. and Sharma, M. and Tsai, K. and Priatel, J.J. and Schreiber, R.A. and Rozmus, J. and Hosking, M.C.K. and Shopsowitz, K.E. and McKinnon, M.L. and Vercauteren, S. and Seear, M. and Notarangelo, L.D. and Lynn, F.C. and Berman, J.N. and Turvey, S.E.
DOI: 10.1172/jci.insight.150849
2022Heterogeneity of Diabetes: ß-Cells, Phenotypes, and Precision Medicine: Proceedings of an International Symposium of the Canadian Institutes of Health Research's Institute of Nutrition, Metabolism and Diabetes and the U.S. National Institutes of Health's National Institute of Diabetes and Digestive and Kidney Diseases
Canadian Journal of Diabetes
DOI: 10.1016/j.jcjd.2021.09.126
2021Recapitulating pancreatic cell–cell interactions through bioengineering approaches: the momentous role of non-epithelial cells for diabetes cell therapy
Cellular and Molecular Life Sciences
Ghezelayagh, Z. and Zabihi, M. and Kazemi Ashtiani, M. and Ghezelayagh, Z. and Lynn, F.C. and Tahamtani, Y.
DOI: 10.1007/s00018-021-03951-2
2021Using hiPSC-CMs to Examine Mechanisms of Catecholaminergic Polymorphic Ventricular Tachycardia
Current Protocols
Arslanova, A. and Shafaattalab, S. and Ye, K. and Asghari, P. and Lin, L. and Kim, B. and Roston, T.M. and Hove-Madsen, L. and Van Petegem, F. and Sanatani, S. and Moore, E. and Lynn, F. and S?ndergaard, M. and Luo, Y. and Chen, S.R.W. and Tibbits, G.F.
DOI: 10.1002/cpz1.320
2021Author Correction: Super-resolution microscopy compatible fluorescent probes reveal endogenous glucagon-like peptide-1 receptor distribution and dynamics.
Nature communications
Ast J and Arvaniti A and Fine NHF and Nasteska D and Ashford FB and Stamataki Z and Koszegi Z and Bacon A and Jones BJ and Lucey MA and Sasaki S and Brierley DI and Hastoy B and Tomas A and Hodson DJ
DOI: 10.1038/s41467-020-19101-4
PubMed: 33037231
10/2020Spatial and transcriptional heterogeneity of ß-cell neogenesis revealed by a time-resolved reporter system
Sasaki S and Lee M and Wakabayashi Y and Suzuki L and Winata H and Himuro M and Matsuoka T and Shimomura I and Watada H and Lynn F and Miyatsuka T
DOI: 10.21203/rs.3.rs-46466/v1
08/2020Premature termination codon readthrough upregulates progranulin expression and improves lysosomal function in preclinical models of GRN deficiency
Molecular Neurodegeneration
Frew, J. and Baradaran-Heravi, A. and Balgi, A.D. and Wu, X. and Yan, T.D. and Arns, S. and Shidmoossavee, F.S. and Tan, J. and Jaquith, J.B. and Jansen-West, K.R. and Lynn, F.C. and Gao, F.-B. and Petrucelli, L. and Feldman, H.H. and MacKenzie, I.R. and Roberge, M. and Nygaard, H.B.
DOI: 10.1186/s13024-020-00369-5
2020Super-resolution microscopy compatible fluorescent probes reveal endogenous glucagon-like peptide-1 receptor distribution and dynamics
Nature Communications
Ast, J. and Arvaniti, A. and Fine, N.H.F. and Nasteska, D. and Ashford, F.B. and Stamataki, Z. and Koszegi, Z. and Bacon, A. and Jones, B.J. and Lucey, M.A. and Sasaki, S. and Brierley, D.I. and Hastoy, B. and Tomas, A. and D?Agostino, G. and Reimann, F. and Lynn, F.C. and Reissaus, C.A. and Linnemann, A.K. and D?Este, E. and Calebiro, D. and Trapp, S. and Johnsson, K. and Podewin, T. and Broichhagen, J. and Hodson, D.J.
DOI: 10.1038/s41467-020-14309-w
2020Lrrc55 is a novel prosurvival factor in pancreatic islets.
American journal of physiology. Endocrinology and metabolism
Makkar G and Shrivastava V and Hlavay B and Pretorius M and Kyle BD and Braun AP and Lynn FC and Huang C
DOI: 10.1152/ajpendo.00028.2019
PubMed: 31526288
09/2019Ins2 gene bursting activity defines a mature ß-cell state
Modi H and Skovsø S and Ellis C and Krentz NA and Zhao YB and Cen H and Noursadeghi N and Panzhinskiy E and Hu X and Dionne DA and Xuan S and Huising MO and Kieffer TJ and Lynn FC and Johnson JD
DOI: 10.1101/702589
07/2019Mediator subunit MDT-15/MED15 and Nuclear Receptor HIZR-1/HNF4 cooperate to regulate toxic metal stress responses in Caenorhabditis elegans
PLoS Genetics
Shomer, N. and Zacharie Kadhim, A. and Margaret Grants, J. and Cheng, X. and Alhusari, D. and Bhanshali, F. and Poon, A.F.-Y. and Ya Lee, M.Y. and Muhuri, A. and In Park, J. and Shih, J. and Lee, D. and Lee, S.-J.V. and Lynn, F.C. and Taubert, S.
DOI: 10.1371/journal.pgen.1008508
2019Friend and foe: ß-cell Ca 2+ signaling and the development of diabetes
Molecular Metabolism
Sabatini, P.V. and Speckmann, T. and Lynn, F.C.
DOI: 10.1016/j.molmet.2018.12.007
2019TrxG Complex Catalytic and Non-catalytic Activity Play Distinct Roles in Pancreas Progenitor Specification and Differentiation
Cell Reports
Campbell, S.A. and McDonald, C.L. and Krentz, N.A.J. and Lynn, F.C. and Hoffman, B.G.
DOI: 10.1016/j.celrep.2019.07.035
2019In vitro analyses of suspected arrhythmogenic thin filament variants as a cause of sudden cardiac death in infants
Proceedings of the National Academy of Sciences of the United States of America
Shafaattalab, S. and Li, A.Y. and Lin, E. and Stevens, C.M. and Dewar, L.J. and Lynn, F.C. and Sanatani, S. and Laksman, Z. and Morin, R.D. and van Petegem, F. and Hove-Madsen, L. and Peter Tieleman, D. and Davis, J.P. and Tibbits, G.F.
DOI: 10.1073/pnas.1819023116
2019Single cell transcriptome profiling of mouse and hESC-derived pancreatic progenitors
Krentz NAJ and Lee M and Xu EE and Sasaki S and Lynn FC
DOI: 10.1101/289470
03/2018Neuronal PAS Domain Protein 4 Suppression of Oxygen Sensing Optimizes Metabolism during Excitation of Neuroendocrine Cells.
Cell reports
Sabatini PV and Speckmann T and Nian C and Glavas MM and Wong CK and Yoon JS and Kin T and Shapiro AMJ and Gibson WT and Verchere CB and Lynn FC
PubMed: 29298418
01/2018Single-Cell Transcriptome Profiling of Mouse and hESC-Derived Pancreatic Progenitors
Stem Cell Reports
Krentz, N.A.J. and Lee, M.Y.Y. and Xu, E.E. and Sproul, S.L.J. and Maslova, A. and Sasaki, S. and Lynn, F.C.
DOI: 10.1016/j.stemcr.2018.11.008
2018The p300 and CBP transcriptional coactivators are required for ß-cell and a-cell proliferation
Diabetes
Wong, C.K. and Wade-Vallance, A.K. and Luciani, D.S. and Brindle, P.K. and Lynn, F.C. and Gibson, W.T.
DOI: 10.2337/db17-0237
2018Recessive mutations in ATP8A2 cause severe hypotonia, cognitive impairment, hyperkinetic movement disorders and progressive optic atrophy
Orphanet Journal of Rare Diseases
McMillan, H.J. and Telegrafi, A. and Singleton, A. and Cho, M.T. and Lelli, D. and Lynn, F.C. and Griffin, J. and Asamoah, A. and Rinne, T. and Erasmus, C.E. and Koolen, D.A. and Haaxma, C.A. and Keren, B. and Doummar, D. and Mignot, C. and Thompson, I. and Velsher, L. and Dehghani, M. and Vahidi Mehrjardi, M.Y. and Maroofian, R. and Tchan, M. and Simons, C. and Christodoulou, J. and Martín-Hernández, E. and Guillen Sacoto, M.J. and Henderson, L.B. and McLaughlin, H. and Molday, L.L. and Molday, R.S. and Yoon, G.
DOI: 10.1186/s13023-018-0825-3
2018Neuronal PAS Domain Protein 4 Suppression of Oxygen Sensing Optimizes Metabolism during Excitation of Neuroendocrine Cells
Cell Reports
Sabatini, P.V. and Speckmann, T. and Nian, C. and Glavas, M.M. and Wong, C.K. and Yoon, J.S. and Kin, T. and Shapiro, A.M.J. and Gibson, W.T. and Verchere, C.B. and Lynn, F.C.
DOI: 10.1016/j.celrep.2017.12.033
2018The Polycomb-Dependent Epigenome Controls ß Cell Dysfunction, Dedifferentiation, and Diabetes
Cell Metabolism
Lu, T.T.-H. and Heyne, S. and Dror, E. and Casas, E. and Leonhardt, L. and Boenke, T. and Yang, C.-H. and Sagar and Arrigoni, L. and Dalgaard, K. and Teperino, R. and Enders, L. and Selvaraj, M. and Ruf, M. and Raja, S.J. and Xie, H. and Boenisch, U. and Orkin, S.H. and Lynn, F.C. and Hoffman, B.G. and Grün, D. and Vavouri, T. and Lempradl, A.M. and Pospisilik, J.A.
DOI: 10.1016/j.cmet.2018.04.013
2018The Polycomb-dependent epigenome controls ß-cell dysfunction, dedifferentiation and diabetes
bioRxiv
Lu, T.T.-H. and Heyne, S. and Dror, E. and Casas, E. and Leonhardt, L. and Boenke, T. and Yang, C.-H. and Sagar and Arrigoni, L. and Dalgaard, K. and Teperino, R. and Enders, L. and Selvaraj, M. and Ruf, M. and Raja, S.J. and Xie, H. and Boenisch, U. and Orkin, S.H. and Lynn, F.C. and Hoffman, B.G. and Grün, D. and Vavouri, T. and Lempradl, A. and Andrew Pospisilik, J.
DOI: 10.1101/205641
2017Phosphorylation of NEUROG3 Links Endocrine Differentiation to the Cell Cycle in Pancreatic Progenitors
Developmental Cell
Krentz, N.A.J. and van Hoof, D. and Li, Z. and Watanabe, A. and Tang, M. and Nian, C. and German, M.S. and Lynn, F.C.
DOI: 10.1016/j.devcel.2017.02.006
2017SOX4 allows facultativeß-cellproliferation through repression of cdkn1a
Diabetes
Xu, E.E. and Sasaki, S. and Speckmann, T. and Nian, C. and Lynn, F.C.
DOI: 10.2337/db16-1074
2017Reduced Insulin Production Relieves Endoplasmic Reticulum Stress and Induces ß Cell Proliferation
Cell Metabolism
Szabat, M. and Page, M.M. and Panzhinskiy, E. and Skovs?, S?. and Mojibian, M. and Fernandez-Tajes, J. and Bruin, J.E. and Bround, M.J. and Lee, J.T.C. and Xu, E.E. and Taghizadeh, F. and O'Dwyer, S. and Van De Bunt, M. and Moon, K.-M. and Sinha, S. and Han, J. and Fan, Y. and Lynn, F.C. and Trucco, M. and Borchers, C.H. and Foster, L.J. and Nislow, C. and Kieffer, T.J. and Johnson, J.D.
DOI: 10.1016/j.cmet.2015.10.016
2016Generation of a conditional allele of the transcription factor Atonal Homolog 8 (Atoh8)
PLoS ONE
Ejarque, M. and Mir-Coll, J. and Gomis, R. and German, M.S. and Lynn, F.C. and Gasa, R.
DOI: 10.1371/journal.pone.0146273
2016Reawakening the duct cell progenitor?
Endocrinology
Verchere, C.B. and Lynn, F.C.
DOI: 10.1210/en.2015-2008
2016Npas4 transcription factor expression is regulated by calcium signaling pathways and prevents tacrolimus-induced cytotoxicity in pancreatic beta cells
Journal of Biological Chemistry
Speckmann, T. and Sabatini, P.V. and Nian, C. and Smith, R.G. and Lynn, F.C.
DOI: 10.1074/jbc.M115.704098
2016Using CRISPR-Cas9 genome editing to enhance cell based therapies for the treatment of diabetes mellitus
Genome Editing
DOI: 10.1007/978-3-319-34148-4_8
2016Use-dependent activation of neuronal Kv1.2 channel complexes.
The Journal of neuroscience : the official journal of the Society for Neuroscience
Baronas VA and McGuinness BR and Brigidi GS and Gomm Kolisko RN and Vilin YY and Kim RY and Lynn FC and Bamji SX and Yang R and Kurata HT
DOI: 10.1523/jneurosci.4518-13.2015
PubMed: 25716850
02/2015SOX4 cooperates with neurogenin 3 to regulate endocrine pancreas formation in mouse models
Diabetologia
Xu, E.E. and Krentz, N.A.J. and Tan, S. and Chow, S.Z. and Tang, M. and Nian, C. and Lynn, F.C.
DOI: 10.1007/s00125-015-3507-x
2015All-encomPASsing regulation of ß-cells: PAS domain proteins in ß-cell dysfunction and diabetes
Trends in Endocrinology and Metabolism
Sabatini, P.V. and Lynn, F.C.
DOI: 10.1016/j.tem.2014.11.002
2015Quetiapine treatment in youth is associated with decreased insulin secretion
Journal of Clinical Psychopharmacology
Ngai, Y.F. and Sabatini, P. and Nguyen, D. and Davidson, J. and Chanoine, J.-P. and Devlin, A.M. and Lynn, F.C. and Panagiotopoulos, C.
DOI: 10.1097/JCP.0000000000000118
2014Glycoprotein 130 receptor signaling mediates a-cell dysfunction in a rodent model of type 2 diabetes
Diabetes
Chow, S.Z. and Speck, M. and Yoganathan, P. and Nackiewicz, D. and Hansen, A.M. and Ladefoged, M. and Rabe, B. and Rose-John, S. and Voshol, P.J. and Lynn, F.C. and Herrera, P.L. and Müller, W. and Ellingsgaard, H. and Ehses, J.A.
DOI: 10.2337/db13-1121
2014Characterization of polyhormonal insulin-producing cells derived in vitro from human embryonic stem cells
Stem Cell Research
Bruin, J.E. and Erener, S. and Vela, J. and Hu, X. and Johnson, J.D. and Kurata, H.T. and Lynn, F.C. and Piret, J.M. and Asadi, A. and Rezania, A. and Kieffer, T.J.
DOI: 10.1016/j.scr.2013.10.003
2014TALEN/CRISPR-mediated eGFP knock-in add-on at the OCT4 locus does not impact differentiation of human embryonic stem cells towards endoderm
PLoS ONE
Krentz, N.A.J. and Nian, C. and Lynn, F.C.
DOI: 10.1371/journal.pone.0114275
2014Identification and analysis of murine pancreatic islet enhancers
Diabetologia
Tennant, B.R. and Robertson, A.G. and Kramer, M. and Li, L. and Zhang, X. and Beach, M. and Thiessen, N. and Chiu, R. and Mungall, K. and Whiting, C.J. and Sabatini, P.V. and Kim, A. and Gottardo, R. and Marra, M.A. and Lynn, F.C. and Jones, S.J.M. and Hoodless, P.A. and Hoffman, B.G.
DOI: 10.1007/s00125-012-2797-5
2013The transcription factor atonal homolog 8 regulates Gata4 and friend of Gata-2 during vertebrate development
Journal of Biological Chemistry
Rawnsley, D.R. and Xiao, J. and Lee, J.S. and Liu, X. and Mericko-Ishizuka, P. and Kumar, V. and He, J. and Basu, A. and Lu, M. and Lynn, F.C. and Pack, M. and Gasa, R. and Kahn, M.L.
DOI: 10.1074/jbc.M113.463083
2013Npas4 Is a novel activity-Regulated cytoprotective factor in pancreatic ß-Cells
Diabetes
Sabatini, P.V. and Krentz, N.A.J. and Zarrouki, B. and Westwell-Roper, C.Y. and Nian, C. and Uy, R.A. and Shapiro, A.M.J. and Poitout, V. and Lynn, F.C.
DOI: 10.2337/db12-1527
2013Noncoding RNAs
Experimental Diabetes Research
Hardikar, A.A. and Walker, M.D. and Lynn, F.
DOI: 10.1155/2012/629249
2012Maintenance of ß-cell maturity and plasticity in the adult pancreas: Developmental biology concepts in adult physiology
Diabetes
Szabat, M. and Lynn, F.C. and Hoffman, B.G. and Kieffer, T.J. and Allan, D.W. and Johnson, J.D.
DOI: 10.2337/db11-1361
2012Regulation of GIP and GLP1 receptor cell surface expression by N-glycosylation and receptor heteromerization
PLoS ONE
Whitaker, G.M. and Lynn, F.C. and McIntosh, C.H.S. and Accili, E.A.
DOI: 10.1371/journal.pone.0032675
2012A mouse model for monitoring islet cell genesis and developing therapies for diabetes
DMM Disease Models and Mechanisms
Shimajiri, Y. and Kosaka, Y. and Scheel, D.W. and Lynn, F.C. and Kishimoto, N. and Wang, J. and Zhao, S. and German, M.S.
DOI: 10.1242/dmm.002998
2011Sequence and epigenetic determinants in the regulation of the Math6 gene by Neurogenin3
Differentiation
Pujadas, G. and Felipe, F. and Ejarque, M. and Sanchez, L. and Cervantes, S. and Lynn, F.C. and Gomis, R. and Gasa, R.
DOI: 10.1016/j.diff.2011.05.006
2011Serotonin regulates pancreatic beta cell mass during pregnancy
Nature Medicine
Kim, H. and Toyofuku, Y. and Lynn, F.C. and Chak, E. and Uchida, T. and Mizukami, H. and Fujitani, Y. and Kawamori, R. and Miyatsuka, T. and Kosaka, Y. and Yang, K. and Honig, G. and Van Der Hart, M. and Kishimoto, N. and Wang, J. and Yagihashi, S. and Tecott, L.H. and Watada, H. and German, M.S.
DOI: 10.1038/nm.2173
2010Rfx6 directs islet formation and insulin production in mice and humans
Nature
Smith, S.B. and Qu, H.-Q. and Taleb, N. and Kishimoto, N.Y. and Scheel, D.W. and Lu, Y. and Patch, A.-M. and Grabs, R. and Wang, J. and Lynn, F.C. and Miyatsuka, T. and Mitchell, J. and Seerke, R. and Désir, J. and Eijnden, S.V. and Abramowicz, M. and Kacet, N. and Weill, J. and Renard, M.-E. and Gentile, M. and Hansen, I. and Dewar, K. and Hattersley, A.T. and Wang, R. and Wilson, M.E. and Johnson, J.D. and Polychronakos, C. and German, M.S.
DOI: 10.1038/nature08748
2010Homeodomain transcription factor NKX2.2 functions in immature cells to control enteroendocrine differentiation and is expressed in gastrointestinal neuroendocrine tumors
Endocrine-Related Cancer
Wang, Y.-C. and Gallego-Arteche, E. and Iezza, G. and Yuan, X. and Matli, M.R. and Choo, S.-P. and Zuraek, M.B. and Gogia, R. and Lynn, F.C. and German, M.S. and Bergsland, E.K. and Donner, D.B. and Warren, R.S. and Nakakura, E.K.
DOI: 10.1677/ERC-08-0127
2009Meta-regulation: microRNA regulation of glucose and lipid metabolism
Trends in Endocrinology and Metabolism
Lynn, F.C.
DOI: 10.1016/j.tem.2009.05.007
2009Identification of the bHLH factor Math6 as a novel component of the Embryonic Pancreas Transcriptional Network
PLoS ONE
Lynn, F.C. and Sanchez, L. and Gomis, R. and German, M.S. and Gasa, R.
DOI: 10.1371/journal.pone.0002430
2008Novel glucagon receptor antagonists with improved selectivity over the glucose-dependent insulinotropic polypeptide receptor
Journal of Medicinal Chemistry
Kodra, J.T. and J?rgensen, A.S. and Andersen, B. and Behrens, C. and Brand, C.L. and Christensen, I.T. and Guldbrandt, M. and Jeppesen, C.B. and Knudsen, L.B. and Madsen, P. and Nishimura, E. and Sams, C. and Sidelmann, U.G. and Pedersen, R.A. and Lynn, F.C. and Lau, J.
DOI: 10.1021/jm7015599
2008Mouse let-7 miRNA populations exhibit RNA editing that is constrained in the 5'-seed/cleavage/anchor regions and stabilize predicted mmu-let-7a:mRNA duplexes
Genome Research
Reid, J.G. and Nagaraja, A.K. and Lynn, F.C. and Drabek, R.B. and Muzny, D.M. and Shaw, C.A. and Weiss, M.K. and Naghavi, A.O. and Khan, M. and Zhu, H. and Tennakoon, J. and Gunaratne, G.H. and Corry, D.B. and Miller, J. and McManus, M.T. and German, M.S. and Gibbs, R.A. and Matzuk, M.M. and Gunaratne, P.H.
DOI: 10.1101/gr.078246.108
2008Induction of pancreatic islet cell differentiation by the neurogenin-neuroD cascade
Differentiation
Gasa, R. and Mrejen, C. and Lynn, F.C. and Skewes-Cox, P. and Sanchez, L. and Yang, K.Y. and Lin, C.-H. and Gomis, R. and German, M.S.
DOI: 10.1111/j.1432-0436.2007.00228.x
2008Post-translational regulation of the beta-cell specific factor Nkx6.1
Developmental Biology
DOI: 10.1016/j.ydbio.2007.03.262
06/2007Sox9 coordinates a transcriptional network in pancreatic progenitor cells
Proceedings of the National Academy of Sciences of the United States of America
Lynn, F.C. and Smith, S.B. and Wilson, M.E. and Yang, K.Y. and Nekrep, N. and German, M.S.
DOI: 10.1073/pnas.0704054104
2007MicroRNA expression is required for pancreatic islet cell genesis in the mouse
Diabetes
Lynn, F.C. and Skewes-Cox, P. and Kosaka, Y. and McManus, M.T. and Harfe, B.D. and German, M.S.
DOI: 10.2337/db07-0175
2007Reversal of islet GIP receptor down-regulation and resistance to GIP by reducing hyperglycemia in the Zucker rat
Biochemical and Biophysical Research Communications
Piteau, S. and Olver, A. and Kim, S.-J. and Winter, K. and Pospisilik, J.A. and Lynn, F. and Manhart, S. and Demuth, H.-U. and Speck, M. and Pederson, R.A. and McIntosh, C.H.S.
DOI: 10.1016/j.bbrc.2007.08.115
2007The HMG box transcription factor Sox4 contributes to the development of the endocrine pancreas
Diabetes
Wilson, M.E. and Yang, K.Y. and Kalousova, A. and Lau, J. and Kosaka, Y. and Lynn, F.C. and Wang, J. and Mrejen, C. and Episkopou, V. and Clevers, H.C. and German, M.S.
DOI: 10.2337/diabetes.54.12.3402
2005A novel pathway for regulation of glucose-dependent insulinotropic polypeptide (GIP) receptor expression in beta cells.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Lynn FC and Thompson SA and Pospisilik JA and Ehses JA and Hinke SA and Pamir N and McIntosh CH and Pederson RA
PubMed: 12475913
01/2003Glucose-dependent Insulinotropic Polypeptide (GIP): Development of DP IV-resistant analogues with therapeutic potential
Advances in Experimental Medicine and Biology
2003Glucose-dependent insulinotropic polypeptide receptor null mice exhibit compensatory changes in the enteroinsular axis
American Journal of Physiology - Endocrinology and Metabolism
Pamir, N. and Lynn, F.C. and Buchan, A.M.J. and Ehses, J. and Hinke, S.A. and Pospisilik, J.A. and Miyawaki, K. and Yamada, Y. and Seino, Y. and McIntosh, C.H.S. and Pederson, R.A.
DOI: 10.1152/ajpendo.00270.2002
2003Dipeptidyl peptidase IV inhibitor treatment stimulates ß-cell survival and islet neogenesis in streptozotocin-induced diabetic rats
Diabetes
Pospisilik, J.A. and Martin, J. and Doty, T. and Ehses, J.A. and Pamir, N. and Lynn, F.C. and Piteau, S. and Demuth, H.-U. and McIntosh, C.H.S. and Pederson, R.A.
DOI: 10.2337/diabetes.52.3.741
2003Structure-activity relationships of glucose-dependent insulinotropic polypeptide (GIP)
Biological Chemistry
Hinke, S.A. and Gelling, R. and Manhart, S. and Lynn, F. and Pederson, R.A. and Kühn-Wache, K. and Rosche, F. and Demuth, H.-U. and Coy, D. and McIntosh, C.H.S.
DOI: 10.1515/BC.2003.046
2003Glucose-dependent insulinotropic polypeptide (GIP): development of DP IV-resistant analogues with therapeutic potential.
Advances in experimental medicine and biology
Hinke SA and Lynn F and Ehses J and Pamir N and Manhart S and Kühn-Wache K and Rosche F and Demuth HU and Pederson RA and McIntosh CH
PubMed: 12675251
2003Defective glucose-dependent insulinotropic polypeptide receptor expression in diabetic fatty Zucker rats
Diabetes
Lynn, F.C. and Pamir, N. and Ng, E.H.C. and McIntosh, C.H.S. and Kieffer, T.J. and Pederson, R.A.
DOI: 10.2337/diabetes.50.5.1004
2001Glucose-dependent insulinotropic polypeptide stimulation of lipolysis in differentiated 3T3-L1 cells: Wortmannin-sensitive inhibition by insulin
Endocrinology
McIntosh, C.H.S. and Bremsak, I. and Lynn, F.C. and Gill, R. and Hinke, S.A. and Gelling, R. and Nian, C. and McKnight, G. and Jaspers, S. and Pederson, R.A.
DOI: 10.1210/endo.140.1.6464
1999Improved glucose tolerance in rats treated with the dipeptidyl peptidase IV (CD26) inhibitor ile-thiazolidide
Metabolism: Clinical and Experimental
Pauly, R.P. and Demuth, H.-U. and Rosche, F. and Schmidt, J. and White, H.A. and Lynn, F. and McIntosh, C.H.S. and Pederson, R.A.
DOI: 10.1016/S0026-0495(99)90090-2
1999Characterization of the carboxyl-terminal domain of the rat glucose- dependent insulinotropic polypeptide (GIP) receptor. A role for serines 426 and 427 in regulating the rate of internalization
Journal of Biological Chemistry
Wheeler, M.B. and Gelling, R.W. and Hinke, S.A. and Tu, B. and Pederson, R.A. and Lynn, F. and Ehses, J. and McIntosh, C.H.S.
DOI: 10.1074/jbc.274.35.24593
1999HIP1, a human homologue of S. cerevisiae Sla2p, interacts with membrane- associated huntingtin in the brain
Nature Genetics
Kalchman, M.A. and Koide, H.B. and McCutcheon, K. and Graham, R.K. and Nichol, K. and Nishiyama, K. and Kazemi-Esfarjani, P. and Lynn, F.C. and Wellington, C. and Metzler, M. and Goldberg, Y.P. and Kanazawa, I. and Gietz, R.D. and Hayden, M.R.
DOI: 10.1038/ng0597-44
1997 - Research
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Post-transcriptional Control of ß-cell genesis
Once transcribed there are further opportunities for gene regulation, including regulation of mRNA stability and regulation of the translation of mRNA into protein. These forms of regulation are known as post-transcriptional regulation and play crucial roles in both normal physiology and organismal development. Recently a novel class of genes, known as microRNAs (miRNAs), has been described that can post-transcriptionally regulate gene expression.
We have demonstrated that microRNAs are necessary for ß-cell formation and play a vital role in the Sox9-expressing progenitor cells prior to activation of Neurogenin3. Future work is focussed on understanding:
Which microRNAs are important for normal ß-cell genesis
How specific microRNAs impinge on the ß-cell developmental program
How micrcRNAs regulate normal ß-cell function
If specific microRNAs can drive or enhance ß-cell differentiation from human embryonic stem cells.Transcriptional Control of ß-cell genesis
The central dogma of molecular biology posits that nuclear genomic DNA is transcribed into RNA, which is then translated into protein. These processes are highly regulated and dynamic changes in gene expression are necessary for normal development to occur. The classical model of gene regulation relies upon sequence-specific interactions of nuclear proteins called transcription factors with the promoter regions of genes. The gene regulatory outcome of transcription factor binding to DNA is dependent on both the intrinsic properties of the factor and the regulatory or promoter context. Transcription factors have an indispensable role during all the stages of ß-cell differentiation.
Our past work has focussed on two transcription factors that are important for ß-cell develcpment: Sox9 and Math6. Sox9, an SRY/HMGbox transcription factor, is expressed in the progenitor cells within the developing pancreas and is downregulated during ß-cell differentiation. We have demonstrated that Sox9 plays a bifunctional role in these cells: maintaining undifferentiated characteristics and positively regulating the pro-endocrine factor Neurogenin3. We do not currently understand what factors are necessary for switching between these two roles and this is an area of future research. Math6 is a basic-helix-loop-helix factor that is expressed downstream of Neurogenin3 and modulates the endocrine differentiation program possibly through regulating Neurogenin3 expression. We have generated both germline and conditional null Math6 mice and are currently trying to further understand its role in the formation of ß-cells.GrantsCanucks for Kids Fund Catalyst Grant - 2013
Honours & AwardsMichael Smith Foundation for Health Research Scholar - 2012
Juvenile Diabetes Association Career Development Award - 2011
Research Group MembersAmin Abdolkhani
Irish Amper, Volunteer
Carmen Bayly, Postdoctoral Fellow
James Chae, Summer Student
Jamie Chu
Wayne Fan
Ekaterina Filatov, Research Assistant
Noa Gang, Doctoral Student
Raymond Gao, Co-op student
Helen Huang
Rashmi Hundal, Summer Student
Samantha Mar, Graduate Student
Cuilan Nian, Technician
Emily Park, Postdoctoral Fellow
Caleb Parsonage, Co op Student
Yaser tahamtani, Research Associate
Benjamin Vanderkruk, Graduate Research Asst
Jane Velghe
Alyssa Weinrauch, Postdoctoral Fellow
Chenille Wong, Summer Student
Marcus Woodley, Graduate Student
Angela Yang, Volunteer
Ji Soo (Samantha) Yoon, Postdoctoral Fellow
Dahai Zhang, Research Associate
Katarina Zosel, Trainee
Latest technology enables cell-by-cell approach to finding new diabetes treatment
Using the latest technology, Dr. Francis Lynn and his team analyzed the genetic changes that occur when individual cells become specialized insulin-producing cells called beta cells. This provides an important resource for diabetes researchers to better understand how beta cells develop and work towards the day when we can offer children with diabetes a lifelong cure.
