The pancreas is an endodermally derived organ that initially appears as a dorsal and ventral protrusion of the primitive gut epithelium. The pancreatic progenitor cells present in these early pancreatic anlagen proliferate and eventually give rise to all pancreatic cell types. The fibroblast growth factor receptor (FGFR) 2b high-affinity ligand FGF10 has been linked to pancreatic epithelial cell proliferation, and we have shown previously that Notch signalling controls pancreatic cell differentiation by means of lateral inhibition. In the developing pancreas, activated intracellular Notch appears to be required for maintaining cells in the progenitor state, in part by blocking the expression of the pro-endocrine gene neurogenin 3 (ngn3), and hence endocrine cell differentiation. Here, we show that persistent expression of Fgf10 in the embryonic pancreas of transgenic mice also inhibits pancreatic cell differentiation, while stimulating pancreatic epithelial cell proliferation. We provide evidence that one of the effects of the persistent expression of Fgf10 in the developing pancreas is maintained Notch activation, which results in impaired expression of ngn3 within the pancreatic epithelium. Together, our data suggest a role for FGF10/FGFR2b signalling in regulation of pancreatic cell proliferation and differentiation and that FGF10/FGFR2b signalling affects the Notch-mediated lateral inhibition pathway. Developmental Dynamics 228: 185-193, 2003.

Mesenchymal-epithelial interactions are pivotal for proper pancreatic growth and development. We have earlier shown that the fibroblast growth factor (FGF) receptor 2 is expressed in pancreatic progenitor cells and that FGF10, the high-affinity ligand of the FGF receptor 2 isoform FGF receptor 2b, promotes expansion of pancreatic progenitors. The Wnt family of ligands, which signal to the Frizzled (Frz) type receptors, have also been shown to mediate mesenchymal-epithelial interactions and cell proliferation in a variety of different systems. Here, we show that Frz3, like FGF receptor 2, is expressed in the pancreatic epithelium during the proliferative phase of the embryonic pancreas in mice and that overexpression of a dominantnegative form of mouse Frz8 in pancreatic progenitors severely perturbs pancreatic growth. Nevertheless, the transgenic mice remain normoglycemic and display normal glucose tolerance and glucose-stimulated insulin secretion when challenged with exogenous glucose. The maintenance of normoglycemia in these mice appears to be the consequence of a relative increase in endocrine cell number per pancreatic area combined with enhanced insulin biosynthesis and insulin secretion. Collectively, our data provide evidence that Wnt signaling is required for pancreatic growth but not adult ␤-cell function. Diabetes 54: 2844 -2851, 2005 T he embryonic pancreas in mammals forms from a dorsal and ventral protrusion of the primitive gut epithelium (1). These buds grow, branch, and fuse to form the definitive pancreas, a process dependent on mesenchymal-epithelial interactions. Fibroblast growth factor (FGF) signaling has been implicated in the development of many organs that are dependent on mesenchymal-epithelial interactions, including the pancreas (2,3), and several independent studies have demonstrated that FGF signaling is critical for pancreatic growth. FGF ligands have been shown to have a stimulatory effect on pancreatic epithelial cell proliferation in vitro (4), and mice homozygous for a targeted deletion of the Fgf10 gene present with a hypoplastic pancreas due to impaired proliferation of pancreatic epithelial progenitors (5). In contrast, mice overexpressing Fgf10 under the Ipf1/Pdx1 promoter showed enhanced and persistent proliferation of pancreatic progenitors at the expense of pancreatic cell differentiation (6,7).Other factors that stimulate mesenchymal-epithelial interactions are the Wnt family of secreted glycoproteins. Wnts are expressed in a wide variety of mesenchymal tissues and have been shown to stimulate growth of several organs by signaling to epithelial cells (8). They bind to and activate members of the Frizzled (Frz) family of serpetine receptor proteins and are implicated in a variety of developmental processes such as cell differentiation, cell polarity, cell migration, and cell proliferation (9 -12). Several independent studies have demonstrated a key role for Wnt signaling in cell proliferation. During development, Wnt signaling is required in the entire nervous system fo...

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Anale Sphinkterst~irke und Sphinktervolumetrie in der endovaginalen hochaufl6senden MRT bei gesunden Nulliparae Zusammenfassung. Die endovaginale Magnetresonanztomographie (MRT) erm6glicht eine hochaufl6sen-de Abbildung des Beckenbodens, insbesondere der Muskelschichten des analen Sphinkterkomplexes. Bei sieben gesunden Nulliparae wurden St~ke und Volumen der analen Muskulatur bestimmt. Im Vergleich zu publizierten sonographischen Daten sind die Megwerte fª die Starke des Musculus sphincter ani internus im MRT grti8er, die Werte fª die Dicke des Musculus sphincter ani externus dagegen kleiner. Dies ist durch eine detailliertere Abbildung der Muskelschichten im MRT und eine deutlichere Abgrenzung der Umgebungsstrukturen erkl~rbar. Mit Hilfe der erhaltenen Normwerte sollten sich anatomische Vertinderungen des analen Sphinkters im Sinne einer Hypertrophie bzw. Atrophie leicht beurteilen lassen. Die endovaginale MRT ist ein hilfreiches Instrument in der Diagnostik morphologischer Sphinkterver~nderungen der weiblichen analen Inkontinenz. (Schlª Analer Sphinkter. MRT. Endovaginalspule)Anal Sphincter Size and Volumetric Data in Healthy Nulliparae Assessed by Endovaginal MRI Summary. Magnetic resonance imaging (MRI) using an endovaginal surface coil provides high resolution imaging of the muscles of the pelvic floor and especially the anal canal. In 7 healthy nulliparae anal sphincter size and anal sphincter volume were defined. MRI of the sphincter muscles revealed -when compared by sonography -the sphincter ani internus muscle to be thicker and the sphi, ncter ani externus muscle correspondingty smaller. This can be explained by the more detailed resolution of the muscle layers, and the better contrast to the surrounding structures obtained by MRI: By defining the normal values for the size of the anal sphincter anatomical changes associated with hypertrophy and atrophy could be readily shown. 242H. B. G. Franz, M. P. Mª S. Papadopoulou, et al. coloproctology 19 (1997), 242-246 (Nr. 6)

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