Pancreas Development Proteins

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 Pancreas Development Proteins Background

The pancreas is a compound organ consisting of two tissue types: the endocrine pancreas and the exocrine pancreas. The endocrine pancreas is organized into the Islets of Langerhans, which are responsible for producing hormones that control blood glucose levels. Four distinct cell types exist in the endocrine pancreas: α-cells secrete glucagon, β-cells secrete insulin, δ-cells secrete somatostatin, and PP-cells secrete pancreatic polypeptide. The islets make up a small fraction of the total pancreas mass (about 1-2%). Within the islets, β-cells make up the majority cell type and form a core structure around which other cell types are arranged.

The majority of the total organ mass is the exocrine pancreas. It is organized into acini, which secrete digestive proenzymes such as amylase, elastase, and carboxypeptidase. These enzymes are activated by cleavage and then transported through an elaborate ductal network into the small intestine to help food digestion. Within each acinus exist 30-60 acinar cells that are highly organized and form a polarized structure. The basal area of acinar cells contains a round nucleus and the rough endoplasmic reticulum (rough ER). The apical portion is filled with zymogen granules which contain the proenzymes and are required for enzyme transport and exocytosis. The polarized structure of acinar cells facilitates the regulated secretory process that occurs in a time sequence along intracellular compartments: protein synthesis, intracellular transport and sorting, secretory granule formation and exocytosis.

Fig.1 Histology of the pancreas

Organogenesis of the pancreas

In mouse embryonic development, organogenesis of the pancreas occurs during embryonic day 8.5 (E8.5) to E9.5, featured by the outgrowth of two buds (dorsal and ventral) from the endodermal epithelium located in the region of the foregut. By E12.5, the two buds develop into two primordial pancreas organs containing primarily undifferentiated epithelial cells. Shortly after this the two buds fuse to form a single organ. Starting from E14.5, acinar cells expressing exocrine markers, such as amylase, begin to emerge from the ductal epithelium. By E15.5 organized acinar structures are clearly visible. Endocrine cells coexpressing the endocrine markers glucagon and insulin appear early in development (E9.5), but they exist only as single cells dispersed in the ductal epithelium until E14 when they begin to undergo extensive proliferation. Mature islet structures organize following birth where they undergo additional remodeling.

The early budding process of the pancreas requires its interactions with growth factors secreted by the mesodermal mesenchyme and by the vascular endothelium. It is well recognized that early stages of dorsal pancreatic development require close proximity to the notochord. Removal of the notochord in early embryogenesis prevents the development of the prepatterned endodermal cells that are destined to become the dorsal pancreas. Studies have shown that the notochord secretes growth factors, such as activin-β and fibroblast growth factor 2 (FGF2), which in turn represses the Sonic Hedgehog (SHH) signaling pathway and allows expression of key transcriptional regulators during pancreas organogenesis. What signals control the development of the ventral pancreas bud remains to be defined. The Homeobox protein Hex has been shown to control the positioning of the endodermal cells and may dictate ventral bud specification. However, more analysis needs to be carried out to further investigate this question.


Transcription factors in pancreas development

The differentiation and maturation of different cell types within the pancreas is achieved by a tightly regulated transcriptional network. Most of the transcription factors involved in this process are expressed at multiple time points, play more than one role, and regulate the expression of a number of target genes. Table 1.1 lists some of these transcription factors, their expression patterns, known downstream target genes, and the phenotypes of mice with mutated genomes.

Pdx1, also known as IPF1, IDX1 and STF1, is a homeobox transcription factor that is expressed as early as E8.5 in the primitive forgut endoderm. At E9.5, expression of Pdx1 is observed in both the dorsal and ventral pancreatic buds. Until E14-15, Pdx1 expression is ubiquitous throughout the whole ductal epithelium population and becomes restricted to the endocrine compartment afterwards. Starting from E18.5, Pdx1 protein is mainly detected in mature β-cells of the endocrine pancreas. Deletion of the pdx1 gene in mice results in pancreas agenesis. The dorsal and ventral buds form in the absence of Pdx1 but these structures soon regress. These results suggest that Pdx1 functions in regulating the growth of the pancreas buds instead of in the initial induction of bud formation. In another study, β-cell specific inactivation of the pdx1 gene leads to loss of β-cells leading to diabetes, consistent with the findings that Pdx1 is responsible for activating β-cell specific genes including insulin, glucokinase, islet amyloid polypeptide and glucose transporter type 2 (GLUT2). However, Pdx1 target genes during early embryogenesis remain yet to be identified.

The bHLH protein p48 was originally discovered as a subunit of the PTF1 complex. Together with one class I bHLH protein and RBP-Jκ, p48 forms a trimeric protein complex and activates the transcription of acinar cell specific genes such as elastase and amylase. p48 is thought to function to initiate acinar cell differentiation, which starts at around E14, although its expression can be detected as early as E9.5 in both the dorsal and ventral buds. p48-null mice fail to develop an exocrine pancreas, whereas islets form and migrate into the spleen. This indicates that p48 is crucial not only for the formation of the exocrine pancreas but also for the correct spatial organization of the endocrine pancreas. Lineage tracing experiments using a β-galactosidase reporter gene and a p48 promoter-driven-Cre recombinase show that all acinar and duct cells and the majority of islet cells stain positive for β-gal. This result suggests that all three cell types of the pancreas (acinar, islet, duct) derive from p48- positive progenitor cells, further indicating that p48 may play an important role in early pancreas development.

Neurogenin3 (Ngn3) is a key bHLH transcription factor that functions in the specification of endocrine progenitor cells during early embryogenesis. Its expression can first be detected at E9.5, then peaks at E15.5 during endocrine cell differentiation, and decreases shortly after birth with no expression in the adult animal. Overexpression of Ngn3 in the developing pancreas leads to premature differentiation of the endocrine cells. Ngn3 null animals fail to generate any endocrine cells.