Pancreatic Neurogenin 3-expressing Cells Are Unipotent Islet Precursors

Overview

Journal Development

Specialty Biology

Date 2009 Oct 2

PMID 19793886

Citations 84

Authors

Renaud Desgraz

Pedro L Herrera

Affiliations

Soon will be listed here.

Abstract

Pancreatic islet endocrine cells arise during development from precursors expressing neurogenin 3 (Ngn3). As a population, Ngn3(+) cells produce all islet cell types, but the potential of individual Ngn3(+) cells, an issue central to organogenesis in general and to in vitro differentiation towards cell-based therapies, has not been addressed. We performed in vivo clonal analyses in mice to study the proliferation and differentiation of very large numbers of single Ngn3(+) cells using MADM, a genetic system in which a Cre-dependent chromosomal translocation labels, at extremely low mosaic efficiency, a small number of Ngn3(+) cells. We scored large numbers of progeny arising from single Ngn3(+) cells. In newborns, labeled islets frequently contained just a single tagged endocrine cell, indicating for the first time that each Ngn3(+) cell is the precursor of a single endocrine cell. In adults, small clusters of two to three Ngn3(+) progeny were detected, but all expressed the same hormone, indicating a low rate of replication from birth to adult stages. We propose a model whereby Ngn3(+) cells are monotypic (i.e. unipotent) precursors, and use this paradigm to refocus ideas on how cell number and type must be regulated in building complete islets of Langerhans.

Citing Articles

Pancreatic endocrine and exocrine signaling and crosstalk in physiological and pathological status.

Hu C, Chen Y, Yin X, Xu R, Yin C, Wang C Signal Transduct Target Ther. 2025; 10(1):39.

PMID: 39948335 PMC: 11825823. DOI: 10.1038/s41392-024-02098-3.

The SWI/SNF chromatin remodelling complex regulates pancreatic endocrine cell expansion and differentiation in mice in vivo.

Davidson R, Wu W, Kanojia S, George R, Huter K, Sandoval K Diabetologia. 2024; 67(10):2275-2288.

PMID: 38958700 DOI: 10.1007/s00125-024-06211-7.

Epigenetic modulation of cell fate during pancreas development.

Bele S, Wokasch A, Gannon M Trends Dev Biol. 2024; 16:1-27.

PMID: 38873037 PMC: 11173269.

Chemerin as an Inducer of β Cell Proliferation Mediates Mitochondrial Homeostasis and Promotes β Cell Mass Expansion.

Li M, Zhang R, Ge Q, Yue L, Ma D, Khattab F Int J Mol Sci. 2023; 24(11).

PMID: 37298086 PMC: 10252465. DOI: 10.3390/ijms24119136.

Visualizing Cathepsin K-Cre Expression at the Single-Cell Level with GFP Reporters.

Chai W, Hao W, Liu J, Han Z, Chang S, Cheng L JBMR Plus. 2023; 7(1):e10706.

PMID: 36699636 PMC: 9850439. DOI: 10.1002/jbm4.10706.

References

Thummel R, Burket C, Brewer J, Sarras Jr M, Li L, Perry M . Cre-mediated site-specific recombination in zebrafish embryos. Dev Dyn. 2005; 233(4):1366-77. DOI: 10.1002/dvdy.20475. View

Delacour A, Nepote V, Trumpp A, Herrera P . Nestin expression in pancreatic exocrine cell lineages. Mech Dev. 2004; 121(1):3-14. DOI: 10.1016/j.mod.2003.11.004. View

Inada A, Nienaber C, Katsuta H, Fujitani Y, Levine J, Morita R . Carbonic anhydrase II-positive pancreatic cells are progenitors for both endocrine and exocrine pancreas after birth. Proc Natl Acad Sci U S A. 2008; 105(50):19915-9. PMC: 2604974. DOI: 10.1073/pnas.0805803105. View

Meissner A, Mikkelsen T, Gu H, Wernig M, Hanna J, Sivachenko A . Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature. 2008; 454(7205):766-70. PMC: 2896277. DOI: 10.1038/nature07107. View

Prado C, Pugh-Bernard A, Elghazi L, Sosa-Pineda B, Sussel L . Ghrelin cells replace insulin-producing beta cells in two mouse models of pancreas development. Proc Natl Acad Sci U S A. 2004; 101(9):2924-9. PMC: 365721. DOI: 10.1073/pnas.0308604100. View

Gu G, Dubauskaite J, Melton D . Direct evidence for the pancreatic lineage: NGN3+ cells are islet progenitors and are distinct from duct progenitors. Development. 2002; 129(10):2447-57. DOI: 10.1242/dev.129.10.2447. View

Xu X, DHoker J, Stange G, Bonne S, De Leu N, Xiao X . Beta cells can be generated from endogenous progenitors in injured adult mouse pancreas. Cell. 2008; 132(2):197-207. DOI: 10.1016/j.cell.2007.12.015. View

Porter S, Sorenson R, Dann P, Garcia-Ocana A, Stewart A, Vasavada R . Progressive pancreatic islet hyperplasia in the islet-targeted, parathyroid hormone-related protein-overexpressing mouse. Endocrinology. 1998; 139(9):3743-51. DOI: 10.1210/endo.139.9.6212. View

Scharfmann R, Xiao X, Heimberg H, Mallet J, Ravassard P . Beta cells within single human islets originate from multiple progenitors. PLoS One. 2008; 3(10):e3559. PMC: 2571119. DOI: 10.1371/journal.pone.0003559. View

10.

Zong H, Espinosa J, Su H, Muzumdar M, Luo L . Mosaic analysis with double markers in mice. Cell. 2005; 121(3):479-92. DOI: 10.1016/j.cell.2005.02.012. View

11.

Wang S, Jensen J, Seymour P, Hsu W, Dor Y, Sander M . Sustained Neurog3 expression in hormone-expressing islet cells is required for endocrine maturation and function. Proc Natl Acad Sci U S A. 2009; 106(24):9715-20. PMC: 2701002. DOI: 10.1073/pnas.0904247106. View

12.

Schwitzgebel V, Scheel D, Conners J, Kalamaras J, Lee J, Anderson D . Expression of neurogenin3 reveals an islet cell precursor population in the pancreas. Development. 2000; 127(16):3533-42. DOI: 10.1242/dev.127.16.3533. View

13.

DAmour K, Bang A, Eliazer S, Kelly O, Agulnick A, Smart N . Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat Biotechnol. 2006; 24(11):1392-401. DOI: 10.1038/nbt1259. View

14.

Lee T, Luo L . Mosaic analysis with a repressible cell marker for studies of gene function in neuronal morphogenesis. Neuron. 1999; 22(3):451-61. DOI: 10.1016/s0896-6273(00)80701-1. View

15.

Stern C . Somatic Crossing over and Segregation in Drosophila Melanogaster. Genetics. 1936; 21(6):625-730. PMC: 1208727. DOI: 10.1093/genetics/21.6.625. View

16.

Kockel L, Strom A, Delacour A, Nepote V, Hagenbuchle O, Wellauer P . An amylase/Cre transgene marks the whole endoderm but the primordia of liver and ventral pancreas. Genesis. 2006; 44(6):287-96. DOI: 10.1002/dvg.20206. View

17.

Nelson S, Schaffer A, Sander M . The transcription factors Nkx6.1 and Nkx6.2 possess equivalent activities in promoting beta-cell fate specification in Pdx1+ pancreatic progenitor cells. Development. 2007; 134(13):2491-500. DOI: 10.1242/dev.002691. View

18.

Johansson K, Dursun U, Jordan N, Gu G, Beermann F, Gradwohl G . Temporal control of neurogenin3 activity in pancreas progenitors reveals competence windows for the generation of different endocrine cell types. Dev Cell. 2007; 12(3):457-65. DOI: 10.1016/j.devcel.2007.02.010. View

19.

Brennand K, Huangfu D, Melton D . All beta cells contribute equally to islet growth and maintenance. PLoS Biol. 2007; 5(7):e163. PMC: 1877817. DOI: 10.1371/journal.pbio.0050163. View

20.

Gannon M, Herrera P, Wright C . Mosaic Cre-mediated recombination in pancreas using the pdx-1 enhancer/promoter. Genesis. 2000; 26(2):143-4. DOI: 10.1002/(sici)1526-968x(200002)26:2<143::aid-gene13>3.0.co;2-l. View