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

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

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

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 of the United States of America
Shafaattalab S and Li AY and Lin E and Stevens CM and Dewar LJ and Lynn FC and Sanatani S and Laksman Z and Morin RD and van Petegem F and Hove-Madsen L and Tieleman DP and Davis JP and Tibbits GF
DOI: 10.1073/pnas.1819023116
PubMed: 30886088
03/2019

Single-Cell Transcriptome Profiling of Mouse and hESC-Derived Pancreatic Progenitors.
Stem cell reports
Krentz NAJ and Lee MYY and Xu EE and Sproul SLJ and Maslova A and Sasaki S and Lynn FC
DOI: 10.1016/j.stemcr.2018.11.008
PubMed: 30540962
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
Krentz NAJ and Lee M and Xu EE and Sasaki S and Lynn FC
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

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
05/2017

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 p300 and CBP Transcriptional Coactivators are Required for Beta Cell and Alpha Cell Proliferation
Diabetes
Chi Kin Wong and Adam K Wade-Vallance and Dan S Luciani and Paul K Brindle and Francis C Lynn and 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 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

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 : 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 JE and Erener S and Vela J and Hu X and Johnson JD and Kurata HT and Lynn FC and Piret JM and Asadi A and Rezania A and Kieffer TJ
DOI: 10.1016/j.scr.2013.10.003
PubMed: 24257076
10/2013

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

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

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
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 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

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

Sanya Grover, Summer Student
Elizabeth Lin, Research Assistant 3
Cuilan Nian, Technician
Shugo Sasaki
Thilo Speckmann, Graduate Research Assistant
Shannon Sproul
Helena Winata, Co-op Student
Marcus Woodley, Graduate Student
Ji Soo (Samantha) Yoon, PhD Candidate
Dahai Zhang, Postdoctoral fellow