Overview

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

Novel time-resolved reporter mouse reveals spatial and transcriptional heterogeneity during alpha cell differentiation
Diabetologia
Miwa Himuro and Yuka Wakabayashi and Tomomi Taguchi and Takehiro Katahira and Luka Suzuki and Hitoshi Iida and Takeshi Ogihara and Yuya Nishida and Shugo Sasaki and Francis C. Lynn and Yuichi Hiraoka and Shigeru Oshima and Ryuichi Okamoto and Yoshio Fujitani and Hirotaka Watada and Takeshi Miyatsuka
DOI: 10.1007/s00125-023-06028-w
01/2024

NPAS4 is an allostatic regulator of POMC neuronal activity during diet-induced obesity
Ji Soo Yoon and Daniel Gamu and William T. Gibson and Francis C. Lynn
DOI: 10.1101/2024.01.12.574247
01/2024

Type 2 diabetes susceptibility gene GRK5 regulates physiological pancreatic ß-cell proliferation via phosphorylation of HDAC5
iScience
Shugo Sasaki and Cuilan Nian and Eric E. Xu and Daniel J. Pasula and Helena Winata and Sanya Grover and Dan S. Luciani and Francis C. Lynn
DOI: 10.1016/j.isci.2023.107311
08/2023

Methylation 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
06/2023

Truncated CD19 as a selection marker for the isolation of stem cell derived ß-cells
Luo Ting Helen Huang and Dahai Zhang and Cuilan Nian and Francis C Lynn
DOI: 10.1101/2023.04.05.535733
04/2023

Tracking insulin- and glucagon-expressing bihormonal cells during differentiation using anINSULINandGLUCAGONdouble reporter human embryonic stem cell line
Samantha Mar and Ekaterina Filatov and Cuilan Nian and Shugo Sasaki and Dahai Zhang and Francis C. Lynn
DOI: 10.1101/2023.04.19.537542
04/2023

Islet 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
2023

In 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
2023

Proteomic predictors of individualized nutrient-specific insulin secretion in health and disease
medRxiv
Kolic, J. and Sun, W.G. and Cen, H. and Ewald, J. and Beet, L. and Moravcova, R. and Rogalski, J.C. and Sasaki, S. and Sun, H. and Rajesh, V. and Xia, Y.H. and Skovs?, S. and Spigelman, A.F. and Manning Fox, J.E. and Lyon, J. and Xia, J. and Lynn, F.C. and Gloyn, A.L. and Foster, L.J. and MacDonald, P.E. and Johnson, J.D.
DOI: 10.1101/2023.05.24.23290298
2023

Human 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
2023

Calcium-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
2023

Retraction 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
2023

Type 2 diabetes susceptibility gene GRK5 regulates physiological pancreatic ß-cell proliferation via phosphorylation of HDAC5 in mice
Shugo Sasaki and Cuilan Nian and Eric E. Xu and Daniel J. Pasula and Helena Winata and Sanya Grover and Dan S. Luciani and Francis C. Lynn
DOI: 10.1101/2022.12.23.521810
12/2022

Spatial 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
05/2022

Dynamic 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
2022

A 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
2022

Human 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
2022

In silico discovery of small molecules for efficient stem cell differentiation into definitive endoderm
Gherman Novakovsky and Shugo Sasaki and Oriol Fornes and Meltem E. Omur and Helen Huang and Nathaniel Lim and Artem Cherkasov and Paul Pavlidis and Sara Mostafavi and Francis C. Lynn and Wyeth W. Wasserman
DOI: 10.1101/2021.10.06.463418
10/2021

Methylation of histone H3 lysine 4 is required for maintenance of beta cell function in adult mice
bioRxiv
Vanderkruk, B. and Maeshima, N. and Pasula, D.J. and An, M. and McDonald, C.L. and Lynn, F.C. and Luciani, D.S. and Hoffman, B.G.
DOI: 10.1101/2021.01.28.428651
2021

Using 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
2021

Recapitulating 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
2021

Heterogeneity 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
Cefalu, W.T. and Andersen, D.K. and Arreaza-Rubín, G. and Pin, C.L. and Sato, S. and Verchere, C.B. and Woo, M. and Rosenblum, N.D. and Rosenblum, N. and Cefalu, W. and Dhara, C. and James, S.P. and Makarchuk, M.-J. and Verchere, B. and Powers, A. and Estall, J. and Hoesli, C. and Millman, J. and Linnemann, A. and Johnson, J. and Hawkins, M. and Gloyn, A. and Huising, M.O. and Benninger, R.K.P. and Alma?a, J. and Hull-Meichle, R.L. and MacDonald, P. and Lynn, F. and Melero-Martin, J. and Yoshihara, E. and Stabler, C. and Sander, M. and Evans-Molina, C. and Engin, F. and Thompson, P. and Shalev, A. and Redondo, M.J. and Nadeau, K. and Bellin, M. and Udler, M.S. and Dennis, J. and Dash, S. and Zhou, W. and Snyder, M. and Booth, G. and Butte, A. and Florez, J.
DOI: 10.1016/j.jcjd.2021.09.126
2021

Author 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
10/2020

Spatial 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
08/2020

Premature 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 AD and Wu X and Yan TD and Arns S and Shidmoossavee FS and Tan J and Jaquith JB and Jansen-West KR and Lynn FC and Gao FB and Petrucelli L and Nygaard HB
DOI: 10.1186/s13024-020-00369-5
PubMed: 32178712
03/2020

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/s41467-020-14309-w
PubMed: 31980626
01/2020

Spatial and transcriptional heterogeneity of ß-cell neogenesis revealed by a time-resolved reporter system
ResearchSquare
Sasaki, S. and Lee, M.Y.Y. and Wakabayashi, Y. and Suzuki, L. and Winata, H. and Himuro, M. and Matsuoka, T.-A. and Shimomura, I. and Watada, H. and Lynn, F.C. and Miyatsuka, T.
DOI: 10.21203/rs.3.rs-46466
2020

Lrrc55 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
09/2019

TrxG Complex Catalytic and Non-catalytic Activity Play Distinct Roles in Pancreas Progenitor Specification and Differentiation.
Cell reports
Campbell SA and McDonald CL and Krentz NAJ and Lynn FC and Hoffman BG
DOI: 10.1016/j.celrep.2019.07.035
PubMed: 31412250
08/2019

Ins2 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
07/2019

In vitro analyses of suspected arrhythmogenic thin filament variants as a cause of sudden cardiac death in infants
Proceedings of the National Academy of Sciences
Sanam Shafaattalab and Alison Yueh Li and Eric Lin and Charles M. Stevens and Laura J. Dewar and Francis C. Lynn and Shubhayan Sanatani and Zachary Laksman and Ryan D. Morin and Filip van Petegem and Leif Hove-Madsen and D. Peter Tieleman and Jonathan P. Davis and Glen F. Tibbits
DOI: 10.1073/pnas.1819023116
04/2019

Friend and foe: ß-cell Ca2+ signaling and the development of diabetes
Molecular Metabolism
Paul V. Sabatini and Thilo Speckmann and Francis C. Lynn
DOI: 10.1016/j.molmet.2018.12.007
03/2019

Mediator subunit MDT-15/MED15 and Nuclear Receptor HIZR-1/HNF4 cooperate to regulate toxic metal stress responses in Caenorhabditis elegans
Shomer N and Kadhim AZ and Grants JM and Cheng X and Poon AF and Lee MYY and Bhanshali F and Muhuri A and Park JI and Lee D and Lee SV and Lynn FC and Taubert S
DOI: 10.1101/565739
03/2019

Mediator 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
2019

Lrrc55 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, B.D. and Braun, A.P. and Lynn, F.C. and Huang, C.
DOI: 10.1152/AJPENDO.00028.2019
2019

Single-Cell Transcriptome Profiling of Mouse and hESC-Derived Pancreatic Progenitors
Stem Cell Reports
Nicole A.J. Krentz and Michelle Y.Y. Lee and Eric E. Xu and Shannon L.J. Sproul and Alexandra Maslova and Shugo Sasaki and Francis C. Lynn
DOI: 10.1016/j.stemcr.2018.11.008
12/2018

Recessive mutations in ATP8A2 cause severe hypotonia, cognitive impairment, hyperkinetic movement disorders and progressive optic atrophy.
Orphanet journal of rare diseases
McMillan HJ and Telegrafi A and Singleton A and Cho MT and Lelli D and Lynn FC and Griffin J and Asamoah A and Rinne T and Erasmus CE and Koolen DA and Haaxma CA and Keren B and Doummar D and Yoon G
DOI: 10.1186/s13023-018-0825-3
PubMed: 30012219
05/2018

The Polycomb-Dependent Epigenome Controls ß Cell Dysfunction, Dedifferentiation, and Diabetes.
Cell metabolism
Lu TT and Heyne S and Dror E and Casas E and Leonhardt L and Boenke T and Yang CH and Sagar and Arrigoni L and Dalgaard K and Teperino R and Enders L and Selvaraj M and Ruf M and Raja SJ and Pospisilik JA
DOI: 10.1016/j.cmet.2018.04.013
PubMed: 29754954
05/2018

Single cell transcriptome profiling of mouse and hESC-derived pancreatic progenitors
Nicole A. J. Krentz and Michelle Lee and Eric E. Xu and Shugo Sasaki and Francis C. Lynn
DOI: 10.1101/289470
03/2018

Neuronal 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
01/2018

The 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
2018

Neuronal 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
2018

SOX4 Allows Facultative ß-Cell Proliferation Through Repression of Cdkn1a
Diabetes
Eric E. Xu and Shugo Sasaki and Thilo Speckmann and Cuilan Nian and Francis C. Lynn
DOI: 10.2337/db16-1074
08/2017

Phosphorylation of NEUROG3 Links Endocrine Differentiation to the Cell Cycle in Pancreatic Progenitors
Developmental Cell
Nicole A.J. Krentz and Dennis van Hoof and Zhongmei Li and Akie Watanabe and Mei Tang and Cuilan Nian and Michael S. German and Francis C. Lynn
DOI: 10.1016/j.devcel.2017.02.006
04/2017

The 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
2017

Npas4 Transcription Factor Expression Is Regulated by Calcium Signaling Pathways and Prevents Tacrolimus-induced Cytotoxicity in Pancreatic Beta Cells.
The Journal of biological chemistry
Speckmann T and Sabatini PV and Nian C and Smith RG and Lynn FC
DOI: 10.1074/jbc.m115.704098
PubMed: 26663079
02/2016

Reawakening the Duct Cell Progenitor?
Endocrinology
C. Bruce Verchere and Francis C. Lynn
DOI: 10.1210/en.2015-2008
01/2016

Reduced Insulin Production Relieves Endoplasmic Reticulum Stress and Induces ß Cell Proliferation.
Cell metabolism
Szabat M and Page MM and Panzhinskiy E and Skovsø S and Mojibian M and Fernandez-Tajes J and Bruin JE and Bround MJ and Lee JT and Xu EE and Taghizadeh F and O'Dwyer S and Johnson JD
DOI: 10.1016/j.cmet.2015.10.016
PubMed: 26626461
01/2016

Generation of a Conditional Allele of the Transcription Factor Atonal Homolog 8 (Atoh8)
PLOS ONE
Miriam Ejarque and Joan Mir-Coll and Ramon Gomis and Michael S. German and Francis C. Lynn and Rosa Gasa
DOI: 10.1371/journal.pone.0146273
01/2016

Using CRISPR-Cas9 Genome Editing to Enhance Cell Based Therapies for the Treatment of Diabetes Mellitus
Genome Editing
Nicole A. J. Krentz and Francis C. Lynn
DOI: 10.1007/978-3-319-34148-4_8
2016

Npas4 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
2016

SOX4 cooperates with neurogenin 3 to regulate endocrine pancreas formation in mouse models.
Diabetologia
Xu EE and Krentz NA and Tan S and Chow SZ and Tang M and Nian C and Lynn FC
DOI: 10.1007/s00125-015-3507-x
PubMed: 25652387
05/2015

Use-Dependent Activation of Neuronal Kv1.2 Channel Complexes
The Journal of Neuroscience
Victoria A. Baronas and Brandon R. McGuinness and G. Stefano Brigidi and Rachel N. Gomm Kolisko and Yury Y. Vilin and Robin Y. Kim and Francis C. Lynn and Shernaz X. Bamji and Runying Yang and Harley T. Kurata
DOI: 10.1523/JNEUROSCI.4518-13.2015
02/2015

Use-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
02/2015

All-encomPASsing regulation of ß-cells: PAS domain proteins in ß-cell dysfunction and diabetes
Trends in Endocrinology & Metabolism
Paul V. Sabatini and Francis C. Lynn
DOI: 10.1016/j.tem.2014.11.002
01/2015

Quetiapine treatment in youth is associated with decreased insulin secretion.
Journal of clinical psychopharmacology
Ngai YF and Sabatini P and Nguyen D and Davidson J and Chanoine JP and Devlin AM and Lynn FC and Panagiotopoulos C
DOI: 10.1097/jcp.0000000000000118
PubMed: 24633003
06/2014

Glycoprotein 130 Receptor Signaling Mediates  -Cell Dysfunction in a Rodent Model of Type 2 Diabetes
Diabetes
S. Z. Chow and M. Speck and P. Yoganathan and D. Nackiewicz and A. M. Hansen and M. Ladefoged and B. Rabe and S. Rose-John and P. J. Voshol and F. C. Lynn and P. L. Herrera and W. Muller and H. Ellingsgaard and J. A. Ehses
DOI: 10.2337/db13-1121
05/2014

TALEN/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 NA and Nian C and Lynn FC
DOI: 10.1371/journal.pone.0114275
PubMed: 25474420
2014

Characterization 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
2014

Quetiapine 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
2014

The transcription factor Atonal homolog 8 regulates Gata4 and Friend of Gata-2 during vertebrate development.
The Journal of biological chemistry
Rawnsley DR and Xiao J and Lee JS and Liu X and Mericko-Ishizuka P and Kumar V and He J and Basu A and Lu M and Lynn FC and Pack M and Gasa R and Kahn ML
DOI: 10.1074/jbc.m113.463083
PubMed: 23836893
08/2013

Npas4 Is a Novel Activity–Regulated Cytoprotective Factor in Pancreatic ß-Cells
Diabetes
Paul V. Sabatini and Nicole A.J. Krentz and Bader Zarrouki and Clara Y. Westwell-Roper and Cuilan Nian and Ryan A. Uy and A.M. James Shapiro and Vincent Poitout and Francis C. Lynn
DOI: 10.2337/db12-1527
05/2013

Identification and analysis of murine pancreatic islet enhancers.
Diabetologia
Tennant BR and Robertson AG and Kramer M and Li L and Zhang X and Beach M and Thiessen N and Chiu R and Mungall K and Whiting CJ and Sabatini PV and Kim A and Gottardo R and Marra MA and Hoffman BG
DOI: 10.1007/s00125-012-2797-5
PubMed: 23238790
03/2013

The 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
2013

Maintenance of  -Cell Maturity and Plasticity in the Adult Pancreas: Developmental Biology Concepts in Adult Physiology
Diabetes
M. Szabat and F. C. Lynn and B. G. Hoffman and T. J. Kieffer and D. W. Allan and J. D. Johnson
DOI: 10.2337/db11-1361
05/2012

Regulation of GIP and GLP1 Receptor Cell Surface Expression by N-Glycosylation and Receptor Heteromerization
PLoS ONE
Gina M. Whitaker and Francis C. Lynn and Christopher H. S. McIntosh and Eric A. Accili
DOI: 10.1371/journal.pone.0032675
03/2012

Noncoding RNAs
Experimental Diabetes Research
Anandwardhan A. Hardikar and Michael D. Walker and Francis Lynn
DOI: 10.1155/2012/629249
2012

Sequence and epigenetic determinants in the regulation of the Math6 gene by Neurogenin3.
Differentiation; research in biological diversity
Pujadas G and Felipe F and Ejarque M and Sanchez L and Cervantes S and Lynn FC and Gomis R and Gasa R
DOI: 10.1016/j.diff.2011.05.006
PubMed: 21676531
09/2011

A mouse model for monitoring islet cell genesis and developing therapies for diabetes.
Disease models & mechanisms
Shimajiri Y and Kosaka Y and Scheel DW and Lynn FC and Kishimoto N and Wang J and Zhao S and German MS
DOI: 10.1242/dmm.002998
PubMed: 21135059
03/2011

Serotonin regulates pancreatic beta cell mass during pregnancy
Nature Medicine
Hail Kim and Yukiko Toyofuku and Francis C Lynn and Eric Chak and Toyoyoshi Uchida and Hiroki Mizukami and Yoshio Fujitani and Ryuzo Kawamori and Takeshi Miyatsuka and Yasuhiro Kosaka and Katherine Yang and Gerard Honig and Marieke van der Hart and Nina Kishimoto and Juehu Wang and Soroku Yagihashi and Laurence H Tecott and Hirotaka Watada and Michael S German
DOI: 10.1038/nm.2173
06/2010

Rfx6 directs islet formation and insulin production in mice and humans.
Nature
Smith SB and Qu HQ and Taleb N and Kishimoto NY and Scheel DW and Lu Y and Patch AM and Grabs R and Wang J and Lynn FC and Miyatsuka T and Mitchell J and Seerke R and Désir J and German MS
DOI: 10.1038/nature08748
PubMed: 20148032
02/2010

Meta-regulation: microRNA regulation of glucose and lipid metabolism
Trends in Endocrinology & Metabolism
Francis C. Lynn
DOI: 10.1016/j.tem.2009.05.007
11/2009

Homeodomain transcription factor NKX2.2 functions in immature cells to control enteroendocrine differentiation and is expressed in gastrointestinal neuroendocrine tumors.
Endocrine-related cancer
Wang YC and Gallego-Arteche E and Iezza G and Yuan X and Matli MR and Choo SP and Zuraek MB and Gogia R and Lynn FC and German MS and Bergsland EK and Donner DB and Warren RS and Nakakura EK
DOI: 10.1677/erc-08-0127
PubMed: 18987169
03/2009

Homeodomain 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
2009

Mouse 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 JG and Nagaraja AK and Lynn FC and Drabek RB and Muzny DM and Shaw CA and Weiss MK and Naghavi AO and Khan M and Zhu H and Tennakoon J and Gunaratne GH and Corry DB and Miller J and Gunaratne PH
DOI: 10.1101/gr.078246.108
PubMed: 18614752
10/2008

Novel glucagon receptor antagonists with improved selectivity over the glucose-dependent insulinotropic polypeptide receptor.
Journal of medicinal chemistry
Kodra JT and Jørgensen AS and Andersen B and Behrens C and Brand CL and Christensen IT and Guldbrandt M and Jeppesen CB and Knudsen LB and Madsen P and Nishimura E and Sams C and Lau J
DOI: 10.1021/jm7015599
PubMed: 18707090
09/2008

Identification of the bHLH factor Math6 as a novel component of the embryonic pancreas transcriptional network.
PloS one
Lynn FC and Sanchez L and Gomis R and German MS and Gasa R
DOI: 10.1371/journal.pone.0002430
PubMed: 18560595
06/2008

Induction of pancreatic islet cell differentiation by the neurogenin-neuroD cascade.
Differentiation; research in biological diversity
Gasa R and Mrejen C and Lynn FC and Skewes-Cox P and Sanchez L and Yang KY and Lin CH and Gomis R and German MS
DOI: 10.1111/j.1432-0436.2007.00228.x
PubMed: 17924961
04/2008

MicroRNA expression is required for pancreatic islet cell genesis in the mouse.
Diabetes
Lynn FC and Skewes-Cox P and Kosaka Y and McManus MT and Harfe BD and German MS
DOI: 10.2337/db07-0175
PubMed: 17804764
12/2007

Reversal 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 SJ and Winter K and Pospisilik JA and Lynn F and Manhart S and Demuth HU and Speck M and Pederson RA and McIntosh CH
DOI: 10.1016/j.bbrc.2007.08.115
PubMed: 17803965
11/2007

Post-translational regulation of the beta-cell specific factor Nkx6.1
Developmental Biology
DOI: 10.1016/j.ydbio.2007.03.262
06/2007

Sox9 coordinates a transcriptional network in pancreatic progenitor cells.
Proceedings of the National Academy of Sciences of the United States of America
Lynn FC and Smith SB and Wilson ME and Yang KY and Nekrep N and German MS
DOI: 10.1073/pnas.0704054104
PubMed: 17563382
06/2007

The HMG box transcription factor Sox4 contributes to the development of the endocrine pancreas.
Diabetes
Wilson ME and Yang KY and Kalousova A and Lau J and Kosaka Y and Lynn FC and Wang J and Mrejen C and Episkopou V and Clevers HC and German MS
DOI: 10.2337/diabetes.54.12.3402
PubMed: 16306355
12/2005

Glucose-dependent insulinotropic polypeptide receptor null mice exhibit compensatory changes in the enteroinsular axis.
American journal of physiology. Endocrinology and metabolism
Pamir N and Lynn FC and Buchan AM and Ehses J and Hinke SA and Pospisilik JA and Miyawaki K and Yamada Y and Seino Y and McIntosh CH and Pederson RA
DOI: 10.1152/ajpendo.00270.2002
PubMed: 12540373
05/2003

Dipeptidyl Peptidase IV Inhibitor Treatment Stimulates  -Cell Survival and Islet Neogenesis in Streptozotocin-Induced Diabetic Rats
Diabetes
J. A. Pospisilik and J. Martin and T. Doty and J. A. Ehses and N. Pamir and F. C. Lynn and S. Piteau and H.-U. Demuth and C. H.S. McIntosh and R. A. Pederson
DOI: 10.2337/diabetes.52.3.741
03/2003

Structure-activity relationships of glucose-dependent insulinotropic polypeptide (GIP).
Biological chemistry
Hinke SA and Gelling R and Manhart S and Lynn F and Pederson RA and Kühn-Wache K and Rosche F and Demuth HU and Coy D and McIntosh CH
DOI: 10.1515/bc.2003.046
PubMed: 12715891
03/2003

A 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
DOI: 10.1096/fj.02-0243fje
PubMed: 12475913
01/2003

A 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
01/2003

Structure-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
2003

Glucose-dependent Insulinotropic Polypeptide (GIP): Development of DP IV-resistant analogues with therapeutic potential
Advances in Experimental Medicine and Biology
Hinke, S.A. and Lynn, F. and Ehses, J. and Pamir, N. and Manhart, S. and Kühn-Wache, K. and Rosche, F. and Demuth, H.-U. and Pederson, R.A. and McIntosh, C.H.S.
2003

Glucose-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
2003

Defective glucose-dependent insulinotropic polypeptide receptor expression in diabetic fatty Zucker rats.
Diabetes
Lynn FC and Pamir N and Ng EH and McIntosh CH and Kieffer TJ and Pederson RA
DOI: 10.2337/diabetes.50.5.1004
PubMed: 11334402
05/2001

Characterization of the Carboxyl-terminal Domain of the Rat Glucose-dependent Insulinotropic Polypeptide (GIP) Receptor
Journal of Biological Chemistry
Michael B. Wheeler and Richard W. Gelling and Simon A. Hinke and Ba Tu and Raymond A. Pederson and Francis Lynn and Jan Ehses and Christopher H. S. McIntosh
DOI: 10.1074/jbc.274.35.24593
08/1999

Improved glucose tolerance in rats treated with the dipeptidyl peptidase IV (CD26) inhibitor Ile-thiazolidide
Metabolism
Robert P. Pauly and Hans-Ulrich Demuth and Fred Rosche and Jörn Schmidt and Heather A. White and Francis Lynn and Christopher H.S. McIntosh and Raymond A. Pederson
DOI: 10.1016/s0026-0495(99)90090-2
03/1999

Glucose-dependent insulinotropic polypeptide stimulation of lipolysis in differentiated 3T3-L1 cells: wortmannin-sensitive inhibition by insulin.
Endocrinology
McIntosh CH and Bremsak I and Lynn FC and Gill R and Hinke SA and Gelling R and Nian C and McKnight G and Jaspers S and Pederson RA
DOI: 10.1210/endo.140.1.6464
PubMed: 9886851
01/1999

Improved 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
1999

HIP1, a human homologue of S. cerevisiae Sla2p, interacts with membrane-associated huntingtin in the brain.
Nature genetics
Kalchman MA and Koide HB and McCutcheon K and Graham RK and Nichol K and Nishiyama K and Kazemi-Esfarjani P and Lynn FC and Wellington C and Metzler M and Goldberg YP and Kanazawa I and Hayden MR
DOI: 10.1038/ng0597-44
PubMed: 9140394
05/1997

Research

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.

Grants

Canucks for Kids Fund Catalyst Grant - 2013

Honours & Awards

Michael Smith Foundation for Health Research Scholar - 2012

Juvenile Diabetes Association Career Development Award - 2011

Research Group Members

Amin Abdolkhani
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
Bea Liston, Directed Studies Student
Samantha Mar, Graduate Student
Cuilan Nian, Technician
Emily Park, Postdoctoral Fellow
Benjamin Vanderkruk, Graduate Research Asst
Jane Velghe
Chenille Wong, Summer Student
Marcus Woodley, Graduate Student
Angela Yang, Volunteer
Ji Soo (Samantha) Yoon, Postdoctoral Fellow
Dahai Zhang, Research Associate
Katarina Zosel, Trainee