Pancreatic neurogenin 3-expressing cells are unipotent islet precursors.
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.
Desgraz
Renaud
R
Department of Genetic Medicine and Development, University of Geneva Medical School, 1 rue Michel-Servet, 1211 Geneva-4, Switzerland.
Herrera
Pedro L
PL
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000166:cytology; D007515:Islets of Langerhans / Q000166:cytology* / Q000254:growth & development*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology
D051792:Basic Helix-Loop-Helix Proteins; D009419:Nerve Tissue Proteins; C407737:Neurog3 protein, mouse