Vascular function and sphingosine-1-phosphate regulate development of the dorsal pancreatic mesenchyme.
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.
Edsbagge
Josefina
J
Department of Medical Biochemistry, Box 440, Göteborg University, S-405 30 Göteborg, Sweden.
Johansson
Jenny K
JK
Esni
Farzad
F
Luo
Yang
Y
Radice
Glenn L
GL
Semb
Henrik
H
D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D004707:Endoderm / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008246:Lysophospholipids / Q000378:metabolism / Q000502:physiology*; D008648:Mesoderm / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D010179:Pancreas / Q000196:embryology; D010641:Phenotype; D012313:RNA / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012685:Sepharose / Q000737:chemistry; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000502:physiology*; D013997:Time Factors
D015820:Cadherins; D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; D012313:RNA; D012685:Sepharose; D013110:Sphingosine