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First published online 21 December 2006
doi: 10.1242/dev.02770

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Pancreas and beta-cell development: from the actual to the possible

University of Utah, Department of Human Genetics, 15 N. 2030 E. Room 2100, Salt Lake City, UT 84112, USA.

View larger version (30K): [in this window] [in a new window]   Fig. 1. Pancreatic anatomy, lineages and genes. (A) The dorsal and ventral pancreata (dp and vp, respectively) arise at approximately E8.5 in the mouse (top), from two strips of gut endoderm (marked dp, vp) that are located adjacent to the forming liver (li) within the developing gut endoderm. At E10.5 (middle), the pancreatic primordia bud out into the surrounding mesenchyme and occupy a position between the stomach (st) and intestine (in). Subsequent gut rotation, from E12.5 onward (bottom), brings the two lobes into closer apposition, although each maintains its original ductal connection to the intestine and/or common bile duct (cbd). (B) Lineage tracing indicates that all mature pancreatic cell types derive from progenitors that express Pdx1 and/or Ptf1a (purple), and that a subset of these progenitors go on to express Ngn3 and differentiate into islet cells. Genes listed in red are required for various aspects of the indicated steps, as described in the text.

View larger version (35K): [in this window] [in a new window]   Fig. 2. Stages of pancreas development. Schematic cross-sections of developing embryos and organs, representing the progression of pancreas development. (A) Concomittant with specification of the organ, Pdx1 and Ptf1a initiate expression in two restricted domains of the gut endoderm (en). Nearby tissues, including notochord (nt) and aorta (ao), may promote this specification process (Kim et al., 1997; Lammert et al., 2001; Yoshitomi and Zaret, 2004). (B) Mesenchyme (mes) surrounds the thickening buds as the first Ngn3+ pro-endocrine cells appear. (C) Subsequent outgrowth produces a dense epithelial bud, in which early -cells begin to differentiate. (D) Further growth and branching precedes the secondary transition, which is marked by a massive differentiation of ß-cell and acinar cells, as well as by the progressive restriction of Pdx1 and Ptf1a expression to these respective cell types. (E) The organ has assumed its mature form by birth, with distinct islets of Langerhans scattered among exocrine acini and ducts.

View larger version (63K): [in this window] [in a new window]   Fig. 3. Dynamics of endocrine specification and differentiation. (A-F) Brightfield photomicrographs of Pdx1 immunostaining at various stages of mouse dorsal pancreas (dp) development. From E11.5-E15.5, Pdx1 is expressed throughout the pancreatic epithelium (as well as in the posterior stomach, st), and is subsequently downregulated in acini (ac) and ducts (du) while being maintained in islet ß-cells (is). (G-L) Confocal immunofluorescence photomicrographs at equivalent stages, for the pan-epithelial marker E-cadherin (green) and the islet precursor marker Ngn3 (red). Ngn3 expression is rare at E11.5, dramatically peaks during the secondary transition (E13.5-E15.5) and declines again at E17.5, becoming undetectable in neonatal and adult pancreas. Arrowheads indicate proto-acinar clusters at the periphery of the branched epithelium, from which Ngn3 expression is consistently excluded. (M-R) Confocal detection of glucagon (green) and insulin (red). Glucagon+ -cells are relatively common at E11.5 and E13.5, wheras large numbers of insulin+ ß-cells are not detected until after E13.5. From E17.5 onwards, endocrine cells aggregate into recognizable islets, with ß-cells at their cores and -cells distributed peripherally. Scale bar in all images, 50 µm.

View larger version (11K): [in this window] [in a new window]   Fig. 4. Pathways of islet-subtype specification. A hypothetical lineage diagram for Ngn3+ endocrine precursors, which give rise to all islet cell types (here, a single Ngn3+ cell is depicted giving rise to each subtype, whereas, in reality, the potential of a given Ngn3+ cell may be more restricted). In red are genes required for various steps of this process; some of which (top) appear to function similarly in all subtypes, constituting a core program of endocrine development, whereas others (bottom) are differentially required for specific subtypes (also see Table 1). Although more genes have been implicated in ß-cell development than in that of other subtypes, this is probably due to the greater effort focused on this cell type, rather than an inherently greater complexity in its developmental program.