Advertisement

Diabetologia

pp 1–14 | Cite as

miR-17-92 and miR-106b-25 clusters regulate beta cell mitotic checkpoint and insulin secretion in mice

  • Amitai D. Mandelbaum
  • Sharon Kredo-Russo
  • Danielle Aronowitz
  • Nadav Myers
  • Eran Yanowski
  • Agnes Klochendler
  • Avital Swisa
  • Yuval Dor
  • Eran HornsteinEmail author
Article

Abstract

Aims/hypothesis

Adult beta cells in the pancreas are the sole source of insulin in the body. Beta cell loss or increased demand for insulin impose metabolic challenges because adult beta cells are generally quiescent and infrequently re-enter the cell division cycle. The aim of this study is to test the hypothesis that a family of proto-oncogene microRNAs that includes miR-17-92 and miR-106b-25 clusters regulates beta cell proliferation or function in the adult endocrine pancreas.

Methods

To elucidate the role of miR-17-92 and miR-106b-25 clusters in beta cells, we used a conditional miR-17-92/miR-106b-25 knockout mouse model. We employed metabolic assays in vivo and ex vivo, together with advanced microscopy of pancreatic sections, bioinformatics, mass spectrometry and next generation sequencing, to examine potential targets of miR-17-92/miR-106b-25, by which they might regulate beta cell proliferation and function.

Results

We demonstrate that miR-17-92/miR-106b-25 regulate the adult beta cell mitotic checkpoint and that miR-17-92/miR-106b-25 deficiency results in reduction in beta cell mass in vivo. Furthermore, we reveal a critical role for miR-17-92/miR-106b-25 in glucose homeostasis and in controlling insulin secretion. We identify protein kinase A as a new relevant molecular pathway downstream of miR-17-92/miR-106b-25 in control of adult beta cell division and glucose homeostasis.

Conclusions/interpretation

The study contributes to the understanding of proto-oncogene miRNAs in the normal, untransformed endocrine pancreas and illustrates new genetic means for regulation of beta cell mitosis and function by non-coding RNAs.

Data availability

Sequencing data that support the findings of this study have been deposited in GEO with the accession code GSE126516.

Keywords

Beta cells Cell cycle Diabetes Glucose-stimulated insulin secretion GSIS microRNA PKA Protein kinase A 

Abbreviations

BrdU

Bromodeoxyuridine

FDR

False discovery rate

FRET

Fluorescence resonance energy transfer

GO

Gene ontology

GSIS

Glucose-stimulated insulin secretion

KO

Knockout

MARK2

Microtubule affinity regulating kinase 2

MEF

Mouse embryonic fibroblast

miRNA

MicroRNA

PHH3

Phosphorylated histone H3

PKA

Protein kinase A

PRKAR1α

Protein kinase cAMP-dependent type I regulatory subunit α

qRT-PCR

Quantitative real-time RT-PCR

smFISH

Single molecule fluorescence in situ hybridisation

Notes

Acknowledgements

The authors would like to thank Y. Melamed and O. Higfa for veterinary services and husbandry (Weizmann Institute of Science). The authors thank A. Savidor and Y. Levin at the de Botton Institute for Protein Profiling, Weizmann Institute of Science, and O. Ben-Ami of the Crown Genomics Institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, for MS and next generation sequencing, respectively. We thank O. Elhanani, M. Walker, S. Itzkovitz, H. Kaspi, R. Pasvolsky and E. Geron (Weizmann Institute of Science) for insightful comments on the manuscript.

Contribution statement

ADM, SK and EH made substantial contributions to the conception or design of the work, the acquisition, analysis and interpretation of data and drafting the work for important intellectual content. YD provided substantial contribution to the conception or design of the work and drafting the work for important intellectual content and agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. EY, AK, AS, NM and DA contributed to acquisition, analysis or interpretation of data and drafting the work for important intellectual content. All authors gave final approval of the version to be published. EH is the guarantor of this work.

Funding

The work is funded by an ERC consolidator program (617351), Juvenile Diabetes Research Foundation (99-2007-71 and 47-2012-742), European Diabetes Research Programmes (EFSD)/D-Cure young Investigator award and EFSD-Lilly, Yeda-Sela, Yeda-CEO, Y. Leon Benoziyo Institute for Molecular Medicine, Kekst Family Institute for Medical Genetics, David and Fela Shapell Family Center for Genetic Disorders Research, Crown Human Genome Center, Nathan, Shirley, Philip and Charlene Vener New Scientist Fund, Julius and Ray Charlestein Foundation, Fraida Foundation, Wolfson Family Charitable Trust, Adelis Foundation, Merck (UK), Maria Halphen and Estates of Fannie Sherr, Lola Asseof, Lilly Fulop. Hornstein laboratory is supported by Dr. Sydney Brenner. EH is Head of Nella and Leon Benoziyo Center for Neurological Diseases and incumbent of Ira & Gail Mondry Professorial chair. The study sponsor was not involved in the design of the study, the collection, analysis and interpretation of data, writing the report or the decision to submit the report for publication.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Supplementary material

125_2019_4916_MOESM1_ESM.pdf (573 kb)
ESM Figs (PDF 572 kb)

References

  1. 1.
    Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116(2):281–297.  https://doi.org/10.1016/S0092-8674(04)00045-5 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Lynn FC (2009) Meta-regulation: microRNA regulation of glucose and lipid metabolism. Trends Endocrinol Metab 20(9):452–459.  https://doi.org/10.1016/j.tem.2009.05.007 CrossRefPubMedGoogle Scholar
  3. 3.
    Joglekar MV, Parekh VS, Hardikar AA (2011) Islet-specific microRNAs in pancreas development, regeneration and diabetes. Indian J Exp Biol 49(6):401–408PubMedGoogle Scholar
  4. 4.
    Walker MD (2008) Role of MicroRNA in pancreatic beta-cells: where more is less. Diabetes 57(10):2567–2568.  https://doi.org/10.2337/db08-0934 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Melkman-Zehavi T, Oren R, Kredo-Russo S et al (2011) miRNAs control insulin content in pancreatic beta-cells via downregulation of transcriptional repressors. EMBO J 30(5):835–845.  https://doi.org/10.1038/emboj.2010.361 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Mandelbaum AD, Melkman-Zehavi T, Oren R et al (2012) Dysregulation of Dicer1 in beta cells impairs islet architecture and glucose metabolism. Exp Diabetes Res 2012:470302CrossRefGoogle Scholar
  7. 7.
    Ackermann AM, Gannon M (2007) Molecular regulation of pancreatic beta-cell mass development, maintenance, and expansion. J Mol Endocrinol 38(1–2):193–206.  https://doi.org/10.1677/JME-06-0053 CrossRefPubMedGoogle Scholar
  8. 8.
    Bernard-Kargar C, Ktorza A (2001) Endocrine pancreas plasticity under physiological and pathological conditions. Diabetes 50(Suppl 1):S30–S35.  https://doi.org/10.2337/diabetes.50.2007.S30 CrossRefPubMedGoogle Scholar
  9. 9.
    Meier JJ, Butler AE, Saisho Y et al (2008) Beta-cell replication is the primary mechanism subserving the postnatal expansion of beta-cell mass in humans. Diabetes 57(6):1584–1594.  https://doi.org/10.2337/db07-1369 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Dor Y, Brown J, Martinez OI, Melton DA (2004) Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature 429(6987):41–46.  https://doi.org/10.1038/nature02520 CrossRefPubMedGoogle Scholar
  11. 11.
    Nurse P (1990) Universal control mechanism regulating onset of M-phase. Nature 344(6266):503–508.  https://doi.org/10.1038/344503a0 CrossRefPubMedGoogle Scholar
  12. 12.
    Lu Y, Thomson JM, Wong HY, Hammond SM, Hogan BL (2007) Transgenic over-expression of the microRNA miR-17-92 cluster promotes proliferation and inhibits differentiation of lung epithelial progenitor cells. Dev Biol 310(2):442–453.  https://doi.org/10.1016/j.ydbio.2007.08.007 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Ventura A, Young AG, Winslow MM et al (2008) Targeted deletion reveals essential and overlapping functions of the miR-17 through 92 family of miRNA clusters. Cell 132(5):875–886.  https://doi.org/10.1016/j.cell.2008.02.019 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Pelengaris S, Khan M, Evan GI (2002) Suppression of Myc-induced apoptosis in beta cells exposes multiple oncogenic properties of Myc and triggers carcinogenic progression. Cell 109(3):321–334.  https://doi.org/10.1016/S0092-8674(02)00738-9 CrossRefPubMedGoogle Scholar
  15. 15.
    Mogilyansky E, Rigoutsos I (2013) The miR-17/92 cluster: a comprehensive update on its genomics, genetics, functions and increasingly important and numerous roles in health and disease. Cell Death Differ 20(12):1603–1614.  https://doi.org/10.1038/cdd.2013.125 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Cloonan N, Brown MK, Steptoe AL et al (2008) The miR-17-5p microRNA is a key regulator of the G1/S phase cell cycle transition. Genome Biol 9(8):R127.  https://doi.org/10.1186/gb-2008-9-8-r127 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    O’Donnell KA, Wentzel EA, Zeller KI, Dang CV, Mendell JT (2005) c-Myc-regulated microRNAs modulate E2F1 expression. Nature 435(7043):839–843.  https://doi.org/10.1038/nature03677 CrossRefPubMedGoogle Scholar
  18. 18.
    Sylvestre Y, De Guire V, Querido E et al (2007) An E2F/miR-20a autoregulatory feedback loop. J Biol Chem 282(4):2135–2143.  https://doi.org/10.1074/jbc.M608939200 CrossRefPubMedGoogle Scholar
  19. 19.
    Petrocca F, Visone R, Onelli MR et al (2008) E2F1-regulated microRNAs impair TGFbeta-dependent cell-cycle arrest and apoptosis in gastric cancer. Cancer Cell 13(3):272–286.  https://doi.org/10.1016/j.ccr.2008.02.013 CrossRefPubMedGoogle Scholar
  20. 20.
    Jacovetti C, Matkovich SJ, Rodriguez-Trejo A, Guay C, Regazzi R (2015) Postnatal beta-cell maturation is associated with islet-specific microRNA changes induced by nutrient shifts at weaning. Nat Commun 6(1):8084.  https://doi.org/10.1038/ncomms9084 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Jacovetti C, Rodriguez-Trejo A, Guay C et al (2017) MicroRNAs modulate core-clock gene expression in pancreatic islets during early postnatal life in rats. Diabetologia 60(10):2011–2020.  https://doi.org/10.1007/s00125-017-4348-6 CrossRefPubMedGoogle Scholar
  22. 22.
    Laybutt DR, Weir GC, Kaneto H et al (2002) Overexpression of c-Myc in beta-cells of transgenic mice causes proliferation and apoptosis, downregulation of insulin gene expression, and diabetes. Diabetes 51(6):1793–1804.  https://doi.org/10.2337/diabetes.51.6.1793 CrossRefPubMedGoogle Scholar
  23. 23.
    Hingorani SR, Petricoin Iii EF, Maitra A et al (2003) Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4(6):437–450.  https://doi.org/10.1016/S1535-6108(03)00309-X CrossRefPubMedGoogle Scholar
  24. 24.
    Xiao C, Srinivasan L, Calado DP et al (2008) Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes. Nat Immunol 9(4):405–414.  https://doi.org/10.1038/ni1575 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Klochendler A, Caspi I, Corem N et al (2016) The Genetic Program of Pancreatic beta-Cell Replication In Vivo. Diabetes 65(7):2081–2093.  https://doi.org/10.2337/db16-0003 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Klochendler A, Weinberg-Corem N, Moran M et al (2012) A transgenic mouse marking live replicating cells reveals in vivo transcriptional program of proliferation. Dev Cell 23(4):681–690.  https://doi.org/10.1016/j.devcel.2012.08.009 CrossRefPubMedGoogle Scholar
  27. 27.
    Noordeen NA, Khera TK, Sun G et al (2010) Carbohydrate-responsive element-binding protein (ChREBP) is a negative regulator of ARNT/HIF-1beta gene expression in pancreatic islet beta-cells. Diabetes 59(1):153–160.  https://doi.org/10.2337/db08-0868 CrossRefPubMedGoogle Scholar
  28. 28.
    Durkin ME, Qian X, Popescu NC, Lowy DR (2013) Isolation of Mouse Embryo Fibroblasts. Bio Protoc 3(18):e908CrossRefGoogle Scholar
  29. 29.
    Kim D, Pertea G, Trapnell C, Pimentel H, Kelley R, Salzberg SL (2013) TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol 14(4):R36.  https://doi.org/10.1186/gb-2013-14-4-r36 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Anders S, Pyl PT, Huber W (2015) HTSeq--a Python framework to work with high-throughput sequencing data. Bioinformatics 31(2):166–169.  https://doi.org/10.1093/bioinformatics/btu638 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Love MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15(12):550.  https://doi.org/10.1186/s13059-014-0550-8 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Huang DA, Sherman WBT, Lempicki RA (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4(1):44–57.  https://doi.org/10.1038/nprot.2008.211 CrossRefGoogle Scholar
  33. 33.
    Huang DA, Sherman WBT, Lempicki RA (2009) Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res 37(1):1–13.  https://doi.org/10.1093/nar/gkn923 CrossRefGoogle Scholar
  34. 34.
    Edgar R, Domrachev M, Lash AE (2002) Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res 30(1):207–210.  https://doi.org/10.1093/nar/30.1.207 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Perez-Riverol Y, Csordas A, Bai J et al (2019) The PRIDE database and related tools and resources in 2019: improving support for quantification data. Nucleic Acids Res 47(D1):D442–D450.  https://doi.org/10.1093/nar/gky1106 CrossRefPubMedGoogle Scholar
  36. 36.
    Itzkovitz S, van Oudenaarden A (2011) Validating transcripts with probes and imaging technology. Nat Methods 8(4 Suppl):S12–S19.  https://doi.org/10.1038/nmeth.1573 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Bahar Halpern K, Itzkovitz S (2016) Single molecule approaches for quantifying transcription and degradation rates in intact mammalian tissues. Methods 98:134–142.  https://doi.org/10.1016/j.ymeth.2015.11.015 CrossRefPubMedGoogle Scholar
  38. 38.
    Sommer C, Straehle C, Kothe U, Hamprecht FA (2011) Ilastik: Interactive Learning and Segmentation Toolkit. 2011 8th IEEE International Symposium on Biomedical Imaging: From Nano to Macro: 230–233Google Scholar
  39. 39.
    Chen Y, Tian L, Wan S et al (2016) MicroRNA-17-92 cluster regulates pancreatic beta-cell proliferation and adaptation. Mol Cell Endocrinol 437:213–223.  https://doi.org/10.1016/j.mce.2016.08.037 CrossRefPubMedGoogle Scholar
  40. 40.
    Kong X, Yan D, Sun J et al (2014) Glucagon-like peptide 1 stimulates insulin secretion via inhibiting RhoA/ROCK signaling and disassembling glucotoxicity-induced stress fibers. Endocrinology 155(12):4676–4685.  https://doi.org/10.1210/en.2014-1314 CrossRefPubMedGoogle Scholar
  41. 41.
    Wang Y, Lee CG (2009) MicroRNA and cancer--focus on apoptosis. J Cell Mol Med 13(1):12–23.  https://doi.org/10.1111/j.1582-4934.2008.00510.x CrossRefPubMedGoogle Scholar
  42. 42.
    Milde-Langosch K, Karn T, Muller V et al (2013) Validity of the proliferation markers Ki67, TOP2A, and RacGAP1 in molecular subgroups of breast cancer. Breast Cancer Res Treat 137(1):57–67.  https://doi.org/10.1007/s10549-012-2296-x CrossRefPubMedGoogle Scholar
  43. 43.
    Stolovich-Rain M, Hija A, Grimsby J, Glaser B, Dor Y Pancreatic beta cells in very old mice retain capacity for compensatory proliferation. J Biol Chem 287(33):27407–27414.  https://doi.org/10.1074/jbc.M112.350736 CrossRefGoogle Scholar
  44. 44.
    Oh YS, Shin S, Lee Y-J, Kim EH, Jun H-S (2011) Betacellulin-induced beta cell proliferation and regeneration is mediated by activation of ErbB-1 and ErbB-2 receptors. PLoS One 6(8):e23894.  https://doi.org/10.1371/journal.pone.0023894 CrossRefGoogle Scholar
  45. 45.
    Hija A, Salpeter S, Klochendler A et al (2014) G0-G1 transition and the restriction point in pancreatic beta-cells in vivo. Diabetes 63(2):578–584.  https://doi.org/10.2337/db12-1035 CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Mi H, Muruganujan A, Casagrande JT, Thomas PD (2013) Large-scale gene function analysis with the PANTHER classification system. Nat Protoc 8(8):1551–1566.  https://doi.org/10.1038/nprot.2013.092 CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Du WW, Yang W, Fang L et al (2014) miR-17 extends mouse lifespan by inhibiting senescence signaling mediated by MKP7. Cell Death Dis 5(7):e1355.  https://doi.org/10.1038/cddis.2014.305 CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Prentki M, Matschinsky FM (1987) Ca2+, cAMP, and phospholipid-derived messengers in coupling mechanisms of insulin secretion. Physiol Rev 67(4):1185–1248.  https://doi.org/10.1152/physrev.1987.67.4.1185 CrossRefPubMedGoogle Scholar
  49. 49.
    Yan L, Vatner DE, O’Connor JP et al (2007) Type 5 adenylyl cyclase disruption increases longevity and protects against stress. Cell 130(2):247–258.  https://doi.org/10.1016/j.cell.2007.05.038 CrossRefPubMedGoogle Scholar
  50. 50.
    Hayashita Y, Osada H, Tatematsu Y et al (2005) A polycistronic microRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation. Cancer Res 65(21):9628–9632.  https://doi.org/10.1158/0008-5472.CAN-05-2352 CrossRefPubMedGoogle Scholar
  51. 51.
    Padmanabhan A, Li X, Bieberich CJ (2013) Protein kinase A regulates MYC protein through transcriptional and post-translational mechanisms in a catalytic subunit isoform-specific manner. J Biol Chem 288(20):14158–14169.  https://doi.org/10.1074/jbc.M112.432377 CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Wu KJ, Mattioli M, Morse HC 3rd, Dalla-Favera R (2002) c-MYC activates protein kinase A (PKA) by direct transcriptional activation of the PKA catalytic subunit beta (PKA-Cbeta) gene. Oncogene 21(51):7872–7882.  https://doi.org/10.1038/sj.onc.1205986 CrossRefPubMedGoogle Scholar
  53. 53.
    Seino S, Shibasaki T (2005) PKA-dependent and PKA-independent pathways for cAMP-regulated exocytosis. Physiol Rev 85(4):1303–1342.  https://doi.org/10.1152/physrev.00001.2005 CrossRefPubMedGoogle Scholar
  54. 54.
    Drucker DJ, Nauck MA (2006) The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 368(9548):1696–1705.  https://doi.org/10.1016/S0140-6736(06)69705-5 CrossRefPubMedGoogle Scholar
  55. 55.
    Hussain MA, Stratakis C, Kirschner L (2012) Prkar1a in the regulation of insulin secretion. Horm Metab Res 44(10):759–765.  https://doi.org/10.1055/s-0032-1321866 CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Song WJ, Seshadri M, Ashraf U et al (2011) Snapin mediates incretin action and augments glucose-dependent insulin secretion. Cell Metab 13(3):308–319.  https://doi.org/10.1016/j.cmet.2011.02.002 CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Drewes G, Ebneth A, Preuss U, Mandelkow EM, Mandelkow E (1997) MARK, a novel family of protein kinases that phosphorylate microtubule-associated proteins and trigger microtubule disruption. Cell 89(2):297–308.  https://doi.org/10.1016/S0092-8674(00)80208-1 CrossRefPubMedGoogle Scholar
  58. 58.
    Deng SS, Wu LY, Wang YC et al (2015) Protein kinase A rescues microtubule affinity-regulating kinase 2-induced microtubule instability and neurite disruption by phosphorylating serine 409. J Biol Chem 290(5):3149–3160.  https://doi.org/10.1074/jbc.M114.629873 CrossRefPubMedGoogle Scholar
  59. 59.
    Hubaux R, Thu KL, Vucic EA et al (2015) Microtubule affinity-regulating kinase 2 is associated with DNA damage response and cisplatin resistance in non-small cell lung cancer. Int J Cancer 137(9):2072–2082.  https://doi.org/10.1002/ijc.29577 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Amitai D. Mandelbaum
    • 1
  • Sharon Kredo-Russo
    • 1
  • Danielle Aronowitz
    • 1
  • Nadav Myers
    • 1
  • Eran Yanowski
    • 1
  • Agnes Klochendler
    • 2
  • Avital Swisa
    • 2
  • Yuval Dor
    • 2
  • Eran Hornstein
    • 1
    Email author
  1. 1.Department of Molecular GeneticsWeizmann Institute of ScienceRehovotIsrael
  2. 2.Department of Developmental Biology and Cancer ResearchThe Institute for Medical Research Israel-Canada, The Hebrew University Hadassah Medical SchoolJerusalemIsrael

Personalised recommendations