Function and regulation of zebrafish nkx2.2a during development of pancreatic islet and ducts

Pauls, Stefan; Zecchin, Elisabetta; Tiso, Natascia; Bortolussi, Marino; Argenton, Francesco

doi:10.1016/j.ydbio.2007.01.024

Cited by 84 publications

(81 citation statements)

References 44 publications

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“…As we detected transcripts of the zebrafish IRX3 orthologue irx3a in the embryonic area with the earliest insulin expression (Fig. S2), we next tested whether irx3a affects cell identity in the pancreas, akin to the transcriptional regulator Nkx2.2, which has been shown to regulate the number of ghrelin-and insulin-producing cells in the pancreatic islet in both mouse and zebrafish (24,25).…”

Section: Resultsmentioning

confidence: 99%

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Long-range gene regulation links genomic type 2 diabetes and obesity risk regions to HHEX , SOX4 , and IRX3

Ragvin

Moro

Fredman

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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185

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Genome-wide association studies identified noncoding SNPs associated with type 2 diabetes and obesity in linkage disequilibrium (LD) blocks encompassing HHEX-IDE and introns of CDKAL1 and FTO [Sladek R, et al. (2007) Nature 445:881-885; Steinthorsdottir V, et al. (2007) Nat. Genet 39:770-775; Frayling TM, et al. (2007) Science 316:889-894]. We show that these LD blocks contain highly conserved noncoding elements and overlap with the genomic regulatory blocks of the transcription factor genes HHEX, SOX4, and IRX3. We report that human highly conserved noncoding elements in LD with the risk SNPs drive expression in endoderm or pancreas in transgenic mice and zebrafish. Both HHEX and SOX4 have recently been implicated in pancreas development and the regulation of insulin secretion, but IRX3 had no prior association with pancreatic function or development. Knockdown of its orthologue in zebrafish, irx3a, increased the number of pancreatic ghrelin-producing epsilon cells and decreased the number of insulin-producing beta-cells and glucagon-producing alpha-cells, thereby suggesting a direct link of pancreatic IRX3 function to both obesity and type 2 diabetes

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Section: Resultsmentioning

confidence: 99%

“…Solutions were prepared and microinjected into the yolk of one-cell stage embryos according as previously described (40). The morpholino for nkx2.2a (MOnk-5UTR, 5′-TGGAGCATTTGATGCAGTCAAGTTG) was the one reported by Pauls et al (25). For the controls we used an unrelated/ unspecific morpholino (GTtAATACcAGgATTAgATTgATTG).…”

Section: Methodsmentioning

confidence: 99%

Long-range gene regulation links genomic type 2 diabetes and obesity risk regions to HHEX , SOX4 , and IRX3

Ragvin

Moro

Fredman

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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185

150

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“…Embryos and adult fish were raised and maintained under standard laboratory conditions. We used the following mutant and transgenic lines: laf/alk8 tm110 (23), Tg(ins:GFP) zf5 (38), Tg(ins:dsRed) m1018 (from W. Driever, Freiburg), Tg(HSE:caAlk6, eGFP) w64 (19), Tg(gutGFP) s854 (also known as Tg(XlEef1a1:GFP) s854 ) (15), Tg(hsp70l:bmp2b) f13 (39), Tg(ptf1a:GFP) jh1 (40), and Tg(-3.5nkx2.2a:GFP) ia3/ia3 (41).…”

Section: Methodsmentioning

confidence: 99%

Suppression of Alk8-mediated Bmp signaling cell-autonomously induces pancreatic β-cells in zebrafish

Chung

Andersson

Row

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Bmp signaling has been shown to regulate early aspects of pancreas development, but its role in endocrine, and especially β-cell, differentiation remains unclear. Taking advantage of the ability in zebrafish embryos to cell-autonomously modulate Bmp signaling in single cells, we examined how Bmp signaling regulates the ability of individual endodermal cells to differentiate into β-cells. We find that specific temporal windows of Bmp signaling prevent β-cell differentiation. Thus, future dorsal bud-derived β-cells are sensitive to Bmp signaling specifically during gastrulation and early somitogenesis stages. In contrast, ventral pancreatic cells, which require an early Bmp signal to form, do not produce β-cells when exposed to Bmp signaling at 50 hpf, a stage when the ventral bud-derived extrapancreatic duct is the main source of new endocrine cells. Importantly, inhibiting Bmp signaling within endodermal cells via genetic means increased the number of β-cells, at early and late stages. Moreover, inhibition of Bmp signaling in the late stage embryo using dorsomorphin, a chemical inhibitor of Bmp receptors, significantly increased β-cell neogenesis near the extrapancreatic duct, demonstrating the feasibility of pharmacological approaches to increase β-cell numbers. Our in vivo single-cell analyses show that whereas Bmp signaling is necessary initially for formation of the ventral pancreas, differentiating endodermal cells need to be protected from exposure to Bmps during specific stages to permit β-cell differentiation. These results provide important unique insight into the intercellular signaling environment necessary for in vivo and in vitro generation of β-cells.

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“…We found ghrelin-immunoreactive cells in the pancreas of the Xenopous frog, while ghrelin cells are few in the pancreas of chickens (Wierup N & Sundler F, 2004, unpublished observations). Importantly, ghrelin mRNA is expressed in pancreas of cat fish (Kaiya et al 2005) and ghrelin cells have been found in the zebrafish (Pauls et al 2007). Thus, although it is clear that the ghrelin cell is highly evolutionarily conserved, further studies are needed to elucidate the phylogeny for the ghrelin cell.…”

Section: Ghrelin Cells In Islets Of Other Speciesmentioning

confidence: 99%

The islet ghrelin cell

Wierup¹,

Sundler²,

Heller³

2013

Journal of Molecular Endocrinology

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The islets of Langerhans are key regulators of glucose homeostasis and have been known as a structure for almost one and a half centuries. During the twentieth century several different cell types were described in the islets of different species and at different developmental stages. Six cell types with identified hormonal product have been described so far by the use of histochemical staining methods, transmission electron microscopy, and immunohistochemistry. Thus, glucagon-producing a-cells, insulin-producing b-cells, somatostatin-producing d-cells, pancreatic polypeptide-producing PP-cells, serotoninproducing enterochromaffin-cells, and gastrin-producing G-cells have all been found in the mammalian pancreas at least at some developmental stage. Species differences are at hand and age-related differences are also to be considered. Eleven years ago a novel cell type, the ghrelin cell, was discovered in the human islets. Subsequent studies have shown the presence of islet ghrelin cells in several animals, including mouse, rat, gerbils, and fish. The developmental regulation of ghrelin cells in the islets of mice has gained a lot of interest and several studies have added important pieces to the puzzle of molecular mechanisms and the genetic regulation that lead to differentiation into mature ghrelin cells. A body of evidence has shown that ghrelin is an insulinostatic hormone, and the potential for blockade of ghrelin signalling as a therapeutic avenue for type 2 diabetes is intriguing. Furthermore, ghrelin-expressing pancreatic tumours have been reported and ghrelin needs to be taken into account when diagnosing pancreatic tumours. In this review article, we summarise the knowledge about islet ghrelin cells obtained so far.

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Function and regulation of zebrafish nkx2.2a during development of pancreatic islet and ducts

Cited by 84 publications

References 44 publications

Long-range gene regulation links genomic type 2 diabetes and obesity risk regions to HHEX , SOX4 , and IRX3

Long-range gene regulation links genomic type 2 diabetes and obesity risk regions to HHEX , SOX4 , and IRX3

Suppression of Alk8-mediated Bmp signaling cell-autonomously induces pancreatic β-cells in zebrafish

The islet ghrelin cell

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