Gastrin: a distinct fate of neurogenin3 positive progenitor cells in the embryonic pancreas.
Neurogenin3(+) (Ngn3(+)) progenitor cells in the developing pancreas give rise to five endocrine cell types secreting insulin, glucagon, somatostatin, pancreatic polypeptide and ghrelin. Gastrin is a hormone produced primarily by G-cells in the stomach, where it functions to stimulate acid secretion by gastric parietal cells. Gastrin is expressed in the embryonic pancreas and is common in islet cell tumors, but the lineage and regulators of pancreatic gastrin(+) cells are not known. We report that gastrin is abundantly expressed in the embryonic pancreas and disappears soon after birth. Some gastrin(+) cells in the developing pancreas co-express glucagon, ghrelin or pancreatic polypeptide, but many gastrin(+) cells do not express any other islet hormone. Pancreatic gastrin(+) cells express the transcription factors Nkx6.1, Nkx2.2 and low levels of Pdx1, and derive from Ngn3(+) endocrine progenitor cells as shown by genetic lineage tracing. Using mice deficient for key transcription factors we show that gastrin expression depends on Ngn3, Nkx2.2, NeuroD1 and Arx, but not Pax4 or Pax6. Finally, gastrin expression is induced upon differentiation of human embryonic stem cells to pancreatic endocrine cells expressing insulin. Thus, gastrin(+) cells are a distinct endocrine cell type in the pancreas and an alternative fate of Ngn3+ cells.
Endocrinology and Metabolism Service, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Yaron
Y
Suissa
Judith
J
Magenheim
Miri
M
Stolovich-Rain
Ayat
A
Hija
Patrick
P
Collombat
Ahmed
A
Mansouri
Lori
L
Sussel
Beatriz
B
Sosa-Pineda
Kyle
K
McCracken
James M
JM
Wells
R Scott
RS
Heller
Yuval
Y
Dor
Benjamin
B
Glaser
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D005755:Gastrins / Q000378:metabolism*; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins; D010179:Pancreas / Q000196:embryology* / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D029961:Zebrafish Proteins
D051792:Basic Helix-Loop-Helix Proteins; D005755:Gastrins; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D029961:Zebrafish Proteins; C000715631:NKX2-2 protein, human; C407737:Neurog3 protein, mouse; C000715627:Nkx2-2 protein, mouse; C491328:Nkx6-1 protein, mouse; C000715630:nkx2.2b protein, zebrafish; C093564:Neurogenic differentiation factor 1