Abstract
The mechanisms underlying zebrafish pancreatic islet vascularization have not been well characterized. We sought to determine the angiogenic factors responsible for islet vascularization and assess whether an absence of endothelial cells affects beta-cell and alpha-cell formation. We used a double transgenic zebrafish Tg(fli1:EGFP; insa:tagRFP) to label endothelial cells and beta-cells, respectively. Beta-cells developed adjacent to endothelial cells and by 72 hours post fertilization (hpf) the zebrafish pancreatic islet was highly vascularized. Zebrafish beta-cells express vascular endothelial growth factors (vegf), vegfaa and vegfab. Double knockdown of vegfaa and vegfab or the primary Vegfa receptors (Vegfr2), kdr and kdrl, resulted in vessel deficient islets. While beta-cell and alpha-cell numbers remained unchanged in vessel deficient islets, insulina expression was downregulated relative to controls. Vegfaa/Vegfab-Vegfr2 signaling is necessary for proper islet vessel development, but not for the initial formation of beta-cells and alpha-cells.
Highlights
The pancreas contains both endocrine and exocrine components
While it has been previously observed that some insulin-expressing cells still develop in cloche mutants which lack endothelial cells[10], signals involved in zebrafish islet vascularization and its relationship with islet development is not completely understood
Ventral bud derived beta-cells arise later in development after multiple rounds of progenitor proliferation and the ventral bud derived beta-cells do not retain the label (H2B-EBFP−). We found that both dorsal bud derived (H2B-EBFP+) and ventral bud derived beta-cells (H2B-EBFP−) are present in the kdr/kdrl injected embryos (Supplemental Fig. 4a–c). These results suggest that Vegfaa/Vegfab-Vegfr[2] signaling is necessary for islet vascularization but not required for beta-cell formation regardless of the origin of the beta-cells
Summary
The pancreas contains both endocrine and exocrine components. The exocrine pancreas constitutes the majority of the pancreas and produces digestive enzymes which are delivered to the duodenum. Studies in mice indicate that reciprocal interactions between endothelial cells and islets are important for proper islet development, maturation, and function[1,2]. Lack of islet VegfA in the early murine pancreas or in mature beta-cells results in a significant loss of intra-islet capillaries, impairments in insulin secretion, and glucose intolerance[4,5,6,7,8]. We used a combination of genetic knockdown and pharmaceutical techniques to assess the role of vegfaa and vegfab in zebrafish islet vessel development and endocrine pancreas formation. 72 hpf 7 dpf that while Vegfaa/Vegfab-Vegfr[2] signaling is necessary for proper islet vessel development, it is dispensable for the formation of both of the major islet endocrine cell types, beta-cells and alpha-cells
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