Hnf6 and Tcf2 (MODY5) are linked in a gene network operating in a precursor cell domain of the embryonic pancreas

Abstract

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.

Pancreas organogenesis: From bud to plexus to gland

“…As both Sox9 and HNF1b bind the Ptf1a promoter-enhancer regions, whether they cooperatively regulate Ptf1a expression to maintain the TF network and stabilize the progenitor gene expression programs by multiple (positive and negative) feedback loops is an attractive possibility that could be addressed by more precise experimental dissection. In addition to Ptf1a, HNF1b seems to form a transcription regulatory cascade with HNF6 in controlling pancreatic progenitor generation and endocrine progenitor induction (Maestro et al, 2003;Poll et al, 2006).…”

Snail2, a mediator of epithelial-mesenchymal transitions, expressed in progenitor cells of the developing endocrine pancreas

“…During this transition period, the pro-endocrine transcription factor Neurogenin 3 (Ngn3) is highly expressed in a population of partially differentitated cells derived from the undifferentiated, multipotent epithelial cells of the pancreatic duct-like epihtelium (Maestro et al, 2003), and it promotes their transition into the endocrine cell lineage. The expression of Ngn3 subsequently defervesces as cells further differentiate into distinct endocrine cell lineages expressing the hormones insulin (beta cells), glucagon (alpha cells), somatostatin (delta cells), and pancreatic polypeptide (PP cells).…”

“…Ngn3 is expressed in cells dispersed throughout the E15.5 pancreas (Figure 2) and reside either adjacent to or within the primitive, undifferentiated duct-like epithelium (Gu et al, 2002;Maestro et al, 2003;Schwitzgebel et al, 2000). At this stage of pancreas development (E15.5), Snail2 is broadly expressed throughout the pancreatic epithelium and is found coexpressed in a large proportion (greater than 80%) of Ngn3 cells (yellow, Figure 2 Endocrine cell formation occurs via the activation of Ngn3 within cells of the primitive ductal epithelium, and the subsequent delamination of these cells from this epithelial layer as the cells differentiate and form islets (Apelqvist et al, 1999;Grapin-Botton et al, 2001;Jensen et al, 2000;Pedersen and Heller, 2005).…”

“…At this stage of pancreas development (E15.5), Snail2 is broadly expressed throughout the pancreatic epithelium and is found coexpressed in a large proportion (greater than 80%) of Ngn3 cells (yellow, Figure 2 Endocrine cell formation occurs via the activation of Ngn3 within cells of the primitive ductal epithelium, and the subsequent delamination of these cells from this epithelial layer as the cells differentiate and form islets (Apelqvist et al, 1999;Grapin-Botton et al, 2001;Jensen et al, 2000;Pedersen and Heller, 2005). Using the transcription factor TCF2/HNF1β as a marker of the proliferating duct-like epithelium that gives rise to Ngn3 cells (Maestro et al, 2003), we detect both Ngn3-positive and Snail2-positive cells adjacent-to and interdigitated-with the cells of the primitive ductal epithelium (Figure 2, panels e-h, open arrows). Cells are detected that co-express all three transcription factors ( Figure 2, panels e-h, solid arrows) indicating that the Snail2/Ngn3 cells arise from TCF2-expressing duct like precursors.…”

“…Relative expression values Proposed model of Snail2 expression during pancreas development. In the embryonic pancreas, TCF2-positive cells of the primative ductal tubules proliferate and expand the pool of cells from which Ngn3 endocrine progenitor cells are derived (Maestro et al 2003). Soon after cells become committed to the endocrine linage, Snail2 expression becomes induced in the delaminating pro-endocrine cells.…”