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.
Department of Genetic Medicine and Development, University of Geneva Medical School, 1 rue Michel-Servet, 1211 Geneva-4, Switzerland.
Renaud
R
Desgraz
Pedro L
PL
Herrera
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