Pancreas Differentiation and MorphogenesisThe pancreas contains endocrine and exocrine cells. The exocrine pancreas represents more than 95% of the gland; it is composed of the acinar secretory cells, producing digestive enzymes such as amylase, and the excretory ducts. The endocrine cells of the pancreas form clusters embedded in the exocrine tissue: the islets of Langerhans. Islets are composed of four types of endocrine cells: the centrally located b cells produce insulin, while the peripheral a, d, and PP cells produce glucagon, somatostatin, and pancreatic polypeptide, respectively.
Pancreas OrganogenesisThe pancreas initially develops from distinct dorsal and ventral primordia that later fuse to form the mature organ. This involves a sequential cascade of inductive events in association with the activation of specific transcription factors. Pancreatic buds evaginate from the early foregut endoderm caudally to the stomach primordium, near the prospective liver: the molecular determinants that define the position of the pancreas along the anterior-posterior axis remain unknown (1,2). The first hormone-containing cells found in early primordia are epithelial and appear located exclusively within the walls of the embryonic ducts or cords. Contrary to what is observed in adult islets, these cells frequently contain simultaneously more than one hormone; this has suggested the existence of a common precursor cell for all four islet cell types. For instance, because glucagon-containing cells are the first to differentiate in early buds, and given the presence of cells co-expressing glucagon and insulin, it was proposed that mature insulin cells derive from glucagon progenitors (3).Commitment to a pancreatic fate occurs as early as embryonic d 8-8.5 (E8-E8.5) in mice. Permissive signals released from adjacent mesodermal structures, including the notochord, aorta, and cardiac mesoderm, are important for induction of the pancreatic program. The notochord induces dorsal pancreas development through the inhibition of SHH (Sonic hedgehog) in pre-pancreatic dorsal endoderm. Shh is expressed in the early gut endoderm and has been shown to pattern it (1,(4)(5)(6). This Shh repression, which appears to be by activin bB and FGF2 (7), is permissive for the expression of Pdx1. Shh is also repressed, and Pdx1 expressed, in the ventral pre-pancreatic endoderm.It is intriguing that the same mesenchymal morphogens have opposite inductive effects on the dorsal and ventral pancreas: in the absence of dorsal mesoderm, the dorsal endoderm expresses liver markers, whereas, without ventral mesoderm (i.e., cardiac mesoderm and septum transversum), the ventral endoderm "defaults" to pancreas instead of liver. Indeed, signals from ventral mesoderm (FGFs) promote hepatic development (8).The first indication of morphogenesis occurs at E9.5, when the dorsal mesenchyme condenses and the underlying endoderm evaginates to form a recognizable dorsal pancreatic bud; the ventral bud appears one day later (E10.5). Both buds subsequently proliferate,...