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

Neuronal PAS Domain Protein 4 Suppression of Oxygen Sensing Optimizes Metabolism during Excitation of Neuroendocrine Cells.
Cell reports
Sabatini PV, Speckmann T, Nian C, Glavas MM, Wong CK, Yoon JS, Kin T, Shapiro AMJ, Gibson WT, Verchere CB, Lynn FC
PubMed: 29298418
01/2018

SOX4 Allows Facultative ß-Cell Proliferation Through Repression of Cdkn1a
Diabetes
Eric E. Xu, Shugo Sasaki, Thilo Speckmann, Cuilan Nian, Francis C. Lynn
DOI: 10.2337/db16-1074
05/2017

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

The p300 and CBP Transcriptional Coactivators are Required for Beta Cell and Alpha Cell Proliferation
Diabetes
Chi Kin Wong, Adam K Wade-Vallance, Dan S Luciani, Paul K Brindle, Francis C Lynn, William T Gibson
DOI: 10.2337/db17-0237
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, Sabatini PV, Nian C, Smith RG, Lynn FC
DOI: 10.1074/jbc.m115.704098
PubMed: 26663079
02/2016

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

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

Generation of a Conditional Allele of the Transcription Factor Atonal Homolog 8 (Atoh8)
PLOS ONE
Miriam Ejarque, Joan Mir-Coll, Ramon Gomis, Michael S. German, Francis C. Lynn, 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, Francis C. Lynn
DOI: 10.1007/978-3-319-34148-4_8
2016

SOX4 cooperates with neurogenin 3 to regulate endocrine pancreas formation in mouse models.
Diabetologia
Xu EE, Krentz NA, Tan S, Chow SZ, Tang M, Nian C, 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 : the official journal of the Society for Neuroscience
Baronas VA, McGuinness BR, Brigidi GS, Gomm Kolisko RN, Vilin YY, Kim RY, Lynn FC, Bamji SX, Yang R, 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, 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, Sabatini P, Nguyen D, Davidson J, Chanoine JP, Devlin AM, Lynn FC, Panagiotopoulos C
DOI: 10.1097/jcp.0000000000000118
PubMed: 24633003
06/2014

Glycoprotein 130 Receptor Signaling Mediates alpha-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, Nian C, Lynn FC
DOI: 10.1371/journal.pone.0114275
PubMed: 25474420
2014

The transcription factor Atonal homolog 8 regulates Gata4 and Friend of Gata-2 during vertebrate development.
The Journal of biological chemistry
Rawnsley DR, Xiao J, Lee JS, Liu X, Mericko-Ishizuka P, Kumar V, He J, Basu A, Lu M, Lynn FC, Pack M, Gasa R, 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, Nicole A.J. Krentz, Bader Zarrouki, Clara Y. Westwell-Roper, Cuilan Nian, Ryan A. Uy, A.M. James Shapiro, Vincent Poitout, Francis C. Lynn
DOI: 10.2337/db12-1527
05/2013

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

Maintenance of beta-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, Francis C. Lynn, Christopher H. S. McIntosh, Eric A. Accili
DOI: 10.1371/journal.pone.0032675
03/2012

Noncoding RNAs
Experimental Diabetes Research
Anandwardhan A. Hardikar, Michael D. Walker, 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, Felipe F, Ejarque M, Sanchez L, Cervantes S, Lynn FC, Gomis R, 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, Kosaka Y, Scheel DW, Lynn FC, Kishimoto N, Wang J, Zhao S, German MS
DOI: 10.1242/dmm.002998
PubMed: 21135059
03/2011

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

Rfx6 directs islet formation and insulin production in mice and humans.
Nature
Smith SB, Qu HQ, Taleb N, Kishimoto NY, Scheel DW, Lu Y, Patch AM, Grabs R, Wang J, Lynn FC, Miyatsuka T, Mitchell J, Seerke R, Désir J, 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, Gallego-Arteche E, Iezza G, Yuan X, Matli MR, Choo SP, Zuraek MB, Gogia R, Lynn FC, German MS, Bergsland EK, Donner DB, Warren RS, Nakakura EK
DOI: 10.1677/erc-08-0127
PubMed: 18987169
03/2009

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, Nagaraja AK, Lynn FC, Drabek RB, Muzny DM, Shaw CA, Weiss MK, Naghavi AO, Khan M, Zhu H, Tennakoon J, Gunaratne GH, Corry DB, Miller J, 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, Jørgensen AS, Andersen B, Behrens C, Brand CL, Christensen IT, Guldbrandt M, Jeppesen CB, Knudsen LB, Madsen P, Nishimura E, Sams C, 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, Sanchez L, Gomis R, German MS, 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, Mrejen C, Lynn FC, Skewes-Cox P, Sanchez L, Yang KY, Lin CH, Gomis R, 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, Skewes-Cox P, Kosaka Y, McManus MT, Harfe BD, 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, Olver A, Kim SJ, Winter K, Pospisilik JA, Lynn F, Manhart S, Demuth HU, Speck M, Pederson RA, 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
Anastasia Mavropoulos and Francis C. Lynn and Skewes-Cox Peter and Michael T. MacManus and Michael S. German
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, Smith SB, Wilson ME, Yang KY, Nekrep N, 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, Yang KY, Kalousova A, Lau J, Kosaka Y, Lynn FC, Wang J, Mrejen C, Episkopou V, Clevers HC, 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, Lynn FC, Buchan AM, Ehses J, Hinke SA, Pospisilik JA, Miyawaki K, Yamada Y, Seino Y, McIntosh CH, Pederson RA
DOI: 10.1152/ajpendo.00270.2002
PubMed: 12540373
05/2003

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

Dipeptidyl Peptidase IV Inhibitor Treatment Stimulates  -Cell Survival and Islet Neogenesis in Streptozotocin-Induced Diabetic Rats
Diabetes
J. A. Pospisilik, J. Martin, T. Doty, J. A. Ehses, N. Pamir, F. C. Lynn, S. Piteau, H.-U. Demuth, C. H.S. McIntosh, R. A. Pederson
DOI: 10.2337/diabetes.52.3.741
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, Thompson SA, Pospisilik JA, Ehses JA, Hinke SA, Pamir N, McIntosh CH, Pederson RA
PubMed: 12475913
01/2003

Glucose-dependent insulinotropic polypeptide (GIP): development of DP IV-resistant analogues with therapeutic potential.
Advances in experimental medicine and biology
Hinke SA, Lynn F, Ehses J, Pamir N, Manhart S, Kühn-Wache K, Rosche F, Demuth HU, Pederson RA, McIntosh CH
PubMed: 12675251
2003

Defective glucose-dependent insulinotropic polypeptide receptor expression in diabetic fatty Zucker rats.
Diabetes
Lynn FC, Pamir N, Ng EH, McIntosh CH, Kieffer TJ, 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) ReceptorA ROLE FOR SERINES 426 AND 427 IN REGULATING THE RATE OF INTERNALIZATION
Journal of Biological Chemistry
Michael B. Wheeler, Richard W. Gelling, Simon A. Hinke, Ba Tu, Raymond A. Pederson, Francis Lynn, Jan Ehses, 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, Hans-Ulrich Demuth, Fred Rosche, Jörn Schmidt, Heather A. White, Francis Lynn, Christopher H.S. McIntosh, 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, Bremsak I, Lynn FC, Gill R, Hinke SA, Gelling R, Nian C, McKnight G, Jaspers S, Pederson RA
DOI: 10.1210/endo.140.1.6464
PubMed: 9886851
01/1999

HIP1, a human homologue of S. cerevisiae Sla2p, interacts with membrane-associated huntingtin in the brain.
Nature genetics
Kalchman MA, Koide HB, McCutcheon K, Graham RK, Nichol K, Nishiyama K, Kazemi-Esfarjani P, Lynn FC, Wellington C, Metzler M, Goldberg YP, Kanazawa I, 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.

Honours & Awards

Juvenile Diabetes Association Career Development Award - 2011

Michael Smith Foundation for Health Research Scholar - 2012

Canucks for Kids Fund Catalyst Grant - 2013

Research Group Members

Thilo Speckmann
Cuilan Nian, Technician
Samantha Yoon
Samantha Yoon, PhD student
Shugo Sasaki
Dahai Zhang
Shannon Sproul