Hnf6 and Tcf2 (MODY5) are linked in a gene network operating in a precursor cell domain of the embryonic pancreas.
During pancreatic organogenesis endocrine cells arise from non self-renewing progenitors that express Ngn3. The precursors that give rise to Ngn3+ cells are presumably located within duct-like structures. However, the nature of such precursors is poorly understood. We show that, at E13-E18, the embryonic stage during which the major burst of beta-cell neogenesis takes place, pancreatic duct cells express Hnf1beta, the product of the maturity-onset diabetes of the young type 5 (MODY5) gene. Ngn3+ cells at this stage invariably cluster with mitotically competent Hnf1beta+ cells, and are often intercalated with these cells in the epithelium that lines the lumen of primitive ducts. We present several observations that collectively indicate that Hnf1beta+ cells are the immediate precursors of Ngn3+ cells. We furthermore show that Hnf1beta expression is markedly reduced in early pancreatic epithelial cells of Hnf6-deficient mice, in which formation of Ngn3+ cells is defective. These findings define a precursor cellular stage of the embryonic pancreas and place Hnf1beta in a genetic hierarchy that regulates the generation of pancreatic endocrine cells.
Endocrinology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
Miguel A
MA
Maestro
Sylvia F
SF
Boj
Reini F
RF
Luco
Christophe E
CE
Pierreux
Judit
J
Cabedo
Joan M
JM
Servitja
Michael S
MS
German
Guy G
GG
Rousseau
Frederic P
FP
Lemaigre
Jorge
J
Ferrer
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D019070:Cell Lineage; D004268:DNA-Binding Proteins / Q000235:genetics*; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D051539:Hepatocyte Nuclear Factor 1-beta; D051559:Hepatocyte Nuclear Factor 6; D018398:Homeodomain Proteins / Q000235:genetics*; D051379:Mice; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010179:Pancreas / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D051539:Hepatocyte Nuclear Factor 1-beta; D051559:Hepatocyte Nuclear Factor 6; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C496496:Hnf1b protein, mouse; C407737:Neurog3 protein, mouse; C496606:Onecut1 protein, mouse