BMP Signaling through BMPR1A is Required for Establishment of Pancreatic Laterality




Danesh, Shahab Malekpour

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Pancreatic development begins in the mouse, at embryonic day 8.5, as two patches within the gut tube that are located between the stomach and the duodenum. These patches begin to bud, proliferate, and differentiate to become the dorsal and ventral pancreas. During pancreatic bud development several tissues that are adjacent to the gut tube provide important signals for pancreatic development. Various bone morphogenetic proteins (Bmps) and Bmp receptors (Bmprs) are expressed in the pancreas and in the tissues that flank the pancreatic bud during pancreatic development. Bmp7, BmpR1a, and BmpRII are expressed in the pancreatic endoderm during pancreatic bud development. Bmp2, Bmp4, BmpR1a and BmpRII are expressed in the dorsal aorta which transiently flanks the pancreatic bud. Bmp4, Bmp7, BmpR1a, BmpR1b, and BmpRII are expressed in the pre-pancreatic mesenchyme. Interestingly, Bmp4 is expressed asymmetrically along the gut in the mesogastrium, preceeding gut turning. Transgenic knock down of BMP signaling via the secreted BMP antagonist Noggin in the pre-pancreatic milieu results in reduced pancreas, spleen, stomach and in failure of pyloric sphincter formation. Interestingly, BMP knockdown also results in defects in lateral growth of the pancreas. Specifically, BMP knockdown prevents formation of the splanchnic mesodermal plate (SMP), the asymmetrically forming mesothelial structure that accompanies leftward growth of the pancreas. Conversely, over expression of Bmp2 in the pre-pancreatic milieu does not result in defects in SMP formation or lateral growth of the pancreas. However, overexpression of Bmp2 in the pancreas epithelium resulted in failure to differentiate into endocrine and exocrine cell lineages. Global knockout of BmpR1a, but not BmprII, prior to pancreatic bud development results in developmental defects in SMP formation and pancreatic laterality. Bmpr1a knockout results in reduced SMP expression of Bapx1, a gene required for SMP formation and lateral growth of the pancreas. Therefore, defects in lateral growth of the pancreas in Bmpr1a mutants are likely mediated by Bapx1 and, accordingly, Bmpr1a mutant pancreata exhibit misregulation of genes that require Bapx1, including Fgf9 and Fgf10. Additionally, deletion of Bmpr1a also leads to misregulation of Barx1, another gene with SMP restricted expression. Deletion of BmpR1a specifically from the pre-pancreatic endoderm or endothelial (aorta) cells did not show defects with respect to pancreatic growth, development, or differentiation. Finally, work herein shows that BMP-BMPR1A signaling to the endothelium specifically is required for vascularization of the pancreatic bud and SMP formation. This study presents the first evidence of a cell-cell signaling molecule playing a role in left-right patterning during organogenesis.

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