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First published online 2 February 2005
doi: 10.1242/dev.01643

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Vascular function and sphingosine-1-phosphate regulate development of the dorsal pancreatic mesenchyme

Josefina Edsbagge^1,*, Jenny K. Johansson^1,*,, Farzad Esni^1,, Yang Luo², Glenn L. Radice² and Henrik Semb^1,,

¹ Department of Medical Biochemistry, Box 440, Göteborg University, S-405 30 Göteborg, Sweden
² Department of Obstetrics and Gynecology, University of Pennsylvania School of Medicine, 1355 Biomedical Research Building II/III, 421 Curie Boulevard, Philadelphia, PA 19104, USA

Author for correspondence (e-mail: henrik.semb{at}endo.mas.lu.se)

Accepted 8 December 2004

Early growth and differentiation of the pancreatic endoderm is regulated by soluble factors from the pancreatic mesenchyme. Previously, we demonstrated that N-cadherin-deficient mice lack a dorsal pancreas, due to a critical role of N-cadherin in dorsal pancreatic mesenchymal cell survival. Here, we show that restoring cardiac and circulatory function in N-cadherin null mice by cardiac-specific expression of N-cadherin, rescues formation of the dorsal pancreas, indicating that the phenotype is secondary to defects related to cardiac/vascular function. Based on this observation, we demonstrate that soluble factors present in plasma, such as sphingosine-1-phosphate, rescue formation of the dorsal pancreas in N-cadherin-deficient mice. We also show that sphingosine-1-phosphate indirectly promotes budding of the pancreatic endoderm by stimulating pancreatic mesenchymal cell proliferation. Finally, we identify sphingosine-1-phosphate receptors within the mesenchyme and show that pertussis toxin blocks the sphingosine-1-phosphate-induced actions, suggesting the involvement of G-protein-coupled sphingosine-1-phosphate receptors. Thus, we propose a new model where blood vessel-derived sphingosine-1-phosphate stimulates growth and budding of the dorsal pancreatic endoderm by induction of mesenchymal cell proliferation.

Key words: Pancreas, Morphogenesis, Blood vessel, Mesenchyme, Sphingosine-1-phosphate, Mouse

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