Independent development of pancreatic alpha- and beta-cells from neurogenin3-expressing precursors: a role for the notch pathway in repression of premature differentiation

• Published in: Diabetes (New York, N.Y.) Vol. 49; no. 2; pp. 163 - 176
• Main Authors: JENSEN, J, HELLER, R. S, FUNDER-NIELSEN, T, PEDERSEN, E. E, LINDSELL, C, WEINMASTER, G, MADSEN, O. D, SERUP, P
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01-02-2000
• Subjects: Animals; Basic Helix-Loop-Helix Transcription Factors; Biological and medical sciences; Biomarkers; Cell Differentiation - physiology; Endocrine pancreas; Epithelial Cells - cytology; Epithelial Cells - metabolism; Fundamental and applied biological sciences. Psychology; Glucagon - metabolism; Homeodomain Proteins; Islets of Langerhans - cytology; Ki-67 Antigen - metabolism; Membrane Proteins - metabolism; Membrane Proteins - physiology; Mice; Mice, Inbred Strains; Morphology. Functional localizations; Nerve Tissue Proteins - metabolism; Pancreas - embryology; Pancreas - metabolism; Rats; Rats, Inbred WF; Receptor, Notch1; Receptor, Notch2; Receptors, Cell Surface - metabolism; Receptors, Notch; Stem Cells - cytology; Stem Cells - metabolism; Trans-Activators - metabolism; Transcription Factors; Vertebrates: endocrinology; Vertebrata; Mammalia; B-Cell; Rat; Mouse; Rodentia; Precursor cell; A-Cell; Differentiation; Endocrine pancreas
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.49.2.163

Independent development of pancreatic alpha- and beta-cells from neurogenin3-expressing precursors: a role for the notch pathway
in repression of premature differentiation.
J Jensen ,
R S Heller ,
T Funder-Nielsen ,
E E Pedersen ,
C Lindsell ,
G Weinmaster ,
O D Madsen and
P Serup
Department of Developmental Biology, Hagedorn Research Institute, Gentofte, Denmark.
Abstract
The nature and identity of the pancreatic beta-cell precursor has remained elusive for many years. One model envisions an
early multihormonal precursor that gives rise to both alpha- and beta-cells and the other endocrine cell types. Alternatively,
beta-cells have been suggested to arise late, directly from the GLUT2- and pancreatic duodenal homeobox factor-1 (PDX1)-expressing
epithelium, which gives rise also to the acinar cells during this stage. In this study, we have identified a subset of the
PDX1+ epithelial cells that are marked by expression of Neurogenin3 (Ngn3). Ngn3, a member of the basic helix-loop-helix (bHLH)
family of transcription factors, is suggested to act upstream of NeuroD in a bHLH cascade. Detailed analysis of Ngn3/paired
box factor 6 (PAX6) and NeuroD/PAX6 co-expression shows that the two bHLH factors are expressed in a largely nonoverlapping
set of cells, but such analysis also suggests that the NeuroD+ cells arise from cells expressing Ngn3 transiently. NeuroD+
cells do not express Ki-67, a marker of proliferating cells, which shows that these cells are postmitotic. In contrast, Ki-67
is readily detected in Ngn3+ cells. Thus, Ngn3+ cells fulfill the criteria for an endocrine precursor cell. These expression
patterns support the notion that both alpha- and beta-cells develop independently from PDX1+/Ngn3+ epithelial cells, rather
than from GLU+/INS+ intermediate stages. The earliest sign of alpha-cell development appears to be Brain4 expression, which
apparently precedes Islet-1 (ISL1) expression. Based on our expression analysis, we propose a temporal sequence of gene activation
and inactivation for developing alpha- and beta-cells beginning with activation of NeuroD expression. Endocrine cells leave
the cell cycle before NeuroD activation, but re-enter the cell cycle at perinatal stages. Dynamic expression of Notch1 in
PDX+ epithelial cells suggests that Notch signaling could inhibit a Ngn-NeuroD cascade as seen in the nervous system and thus
prevent premature differentiation of endocrine cells.