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.
Neuronal PAS Domain Protein 4 Suppression of Oxygen Sensing Optimizes Metabolism during Excitation of Neuroendocrine Cells.
Sabatini PV, Speckmann T, Nian C, Glavas MM, Wong CK, Yoon JS, Kin T, Shapiro AMJ, Gibson WT, Verchere CB, Lynn FC
Phosphorylation of NEUROG3 Links Endocrine Differentiation to the Cell Cycle in Pancreatic Progenitors
Nicole A.J. Krentz, Dennis van Hoof, Zhongmei Li, Akie Watanabe, Mei Tang, Cuilan Nian, Michael S. German, Francis C. Lynn
The p300 and CBP Transcriptional Coactivators are Required for Beta Cell and Alpha Cell Proliferation
Chi Kin Wong, Adam K Wade-Vallance, Dan S Luciani, Paul K Brindle, Francis C Lynn, William T Gibson
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
Reduced Insulin Production Relieves Endoplasmic Reticulum Stress and Induces ß Cell Proliferation.
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
Generation of a Conditional Allele of the Transcription Factor Atonal Homolog 8 (Atoh8)
Miriam Ejarque, Joan Mir-Coll, Ramon Gomis, Michael S. German, Francis C. Lynn, Rosa Gasa
SOX4 cooperates with neurogenin 3 to regulate endocrine pancreas formation in mouse models.
Xu EE, Krentz NA, Tan S, Chow SZ, Tang M, Nian C, Lynn FC
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
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
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
Glycoprotein 130 Receptor Signaling Mediates alpha-Cell Dysfunction in a Rodent Model of Type 2 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
TALEN/CRISPR-mediated eGFP knock-in add-on at the OCT4 locus does not impact differentiation of human embryonic stem cells towards endoderm.
Krentz NA, Nian C, Lynn FC
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
Npas4 Is a Novel Activity–Regulated Cytoprotective Factor in Pancreatic ß-Cells
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
Identification and analysis of murine pancreatic islet enhancers.
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
Maintenance of beta-Cell Maturity and Plasticity in the Adult Pancreas: Developmental Biology Concepts in Adult Physiology
M. Szabat and F. C. Lynn and B. G. Hoffman and T. J. Kieffer and D. W. Allan and J. D. Johnson
Regulation of GIP and GLP1 Receptor Cell Surface Expression by N-Glycosylation and Receptor Heteromerization
Gina M. Whitaker, Francis C. Lynn, Christopher H. S. McIntosh, Eric A. Accili
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
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
Serotonin regulates pancreatic beta cell mass during pregnancy
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
Rfx6 directs islet formation and insulin production in mice and humans.
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
Homeodomain transcription factor NKX2.2 functions in immature cells to control enteroendocrine differentiation and is expressed in gastrointestinal neuroendocrine tumors.
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
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.
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
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
Identification of the bHLH factor Math6 as a novel component of the embryonic pancreas transcriptional network.
Lynn FC, Sanchez L, Gomis R, German MS, Gasa R
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
MicroRNA expression is required for pancreatic islet cell genesis in the mouse.
Lynn FC, Skewes-Cox P, Kosaka Y, McManus MT, Harfe BD, German MS
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
Post-translational regulation of the beta-cell specific factor Nkx6.1
Anastasia Mavropoulos and Francis C. Lynn and Skewes-Cox Peter and Michael T. MacManus and Michael S. German
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
The HMG box transcription factor Sox4 contributes to the development of the endocrine pancreas.
Wilson ME, Yang KY, Kalousova A, Lau J, Kosaka Y, Lynn FC, Wang J, Mrejen C, Episkopou V, Clevers HC, German MS
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
Structure-activity relationships of glucose-dependent insulinotropic polypeptide (GIP).
Hinke SA, Gelling R, Manhart S, Lynn F, Pederson RA, Kühn-Wache K, Rosche F, Demuth HU, Coy D, McIntosh CH
Dipeptidyl Peptidase IV Inhibitor Treatment Stimulates -Cell Survival and Islet Neogenesis in Streptozotocin-Induced Diabetic Rats
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
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
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
Defective glucose-dependent insulinotropic polypeptide receptor expression in diabetic fatty Zucker rats.
Lynn FC, Pamir N, Ng EH, McIntosh CH, Kieffer TJ, Pederson RA
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
Improved glucose tolerance in rats treated with the dipeptidyl peptidase IV (CD26) inhibitor Ile-thiazolidide
Robert P. Pauly, Hans-Ulrich Demuth, Fred Rosche, Jörn Schmidt, Heather A. White, Francis Lynn, Christopher H.S. McIntosh, Raymond A. Pederson
Glucose-dependent insulinotropic polypeptide stimulation of lipolysis in differentiated 3T3-L1 cells: wortmannin-sensitive inhibition by insulin.
McIntosh CH, Bremsak I, Lynn FC, Gill R, Hinke SA, Gelling R, Nian C, McKnight G, Jaspers S, Pederson RA
HIP1, a human homologue of S. cerevisiae Sla2p, interacts with membrane-associated huntingtin in the brain.
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
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 - 2013Research Group Members
Cuilan Nian, Technician
Samantha Yoon, PhD student