Abstract
BackgroundPAX6 is a transcription factor playing a crucial role in the development of the eye and in the differentiation of the pancreatic endocrine cells as well as of enteroendocrine cells. Studies on the mouse Pax6 gene have shown that sequences upstream from the P0 promoter are required for expression in the lens and the pancreas; but there remain discrepancies regarding the precise location of the pancreatic regulatory elements.ResultsDue to genome duplication in the evolution of ray-finned fishes, zebrafish has two pax6 genes, pax6a and pax6b. While both zebrafish pax6 genes are expressed in the developing eye and nervous system, only pax6b is expressed in the endocrine cells of the pancreas. To investigate the cause of this differential expression, we used a combination of in silico, in vivo and in vitro approaches. We show that the pax6b P0 promoter targets expression to endocrine pancreatic cells and also to enteroendocrine cells, retinal neurons and the telencephalon of transgenic zebrafish. Deletion analyses indicate that strong pancreatic expression of the pax6b gene relies on the combined action of two conserved regulatory enhancers, called regions A and C. By means of gel shift assays, we detected binding of the homeoproteins PDX1, PBX and PREP to several cis-elements of these regions. In constrast, regions A and C of the zebrafish pax6a gene are not active in the pancreas, this difference being attributable to sequence divergences within two cis-elements binding the pancreatic homeoprotein PDX1.ConclusionOur data indicate a conserved role of enhancers A and C in the pancreatic expression of pax6b and emphasize the importance of the homeoproteins PBX and PREP cooperating with PDX1, in activating pax6b expression in endocrine pancreatic cells. This study also provides a striking example of how adaptative evolution of gene regulatory sequences upon gene duplication progressively leads to subfunctionalization of the paralogous gene pair.
Highlights
PAX6 is a transcription factor playing a crucial role in the development of the eye and in the differentiation of the pancreatic endocrine cells as well as of enteroendocrine cells
Zebrafish pax6b is expressed in endocrine pancreatic cells in contrast to the zebrafish pax6a gene We first compared, by whole mount in situ hybridization (WISH), the temporal and the spatial expression patterns of the pax6a and pax6b genes between the 10-somite stage and 5 days of zebrafish development (Fig. 1)
The results clearly show that pax6b is expressed in the α, β, δ and ε endocrine cell types (Fig. 1G–R)
Summary
PAX6 is a transcription factor playing a crucial role in the development of the eye and in the differentiation of the pancreatic endocrine cells as well as of enteroendocrine cells. The pancreas has two major functions fulfilled by distinct tissues: i) production of digestive enzymes by the exocrine cells and ii) release of various hormones by distinct endocrine cell types (i.e. secretion of glucagon, insulin, somatostatin, pancreatic polypeptide and ghrelin by α, β, δ, PP and ε cells, respectively). These mature pancreatic endocrine and exocrine cells derive from a pool of endodermal progenitor cells located in the embryonic gut. Pax plays crucial functions in the development of several organs/tissues besides the endocrine pancreas, such as the eyes, olfactory system, brain, spinal cord, enteroendocrine cells and the pituitary (reviewed in [21,22,23,24])
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