Signaling through fibroblast growth factor receptor 2b plays a key role in the development of the exocrine pancreas

Miralles, Francisco; Czernichow, P; Ozaki, Kei-ichi; Itoh, Nobuyuki; Scharfmann, Raphaël

doi:10.1073/pnas.96.11.6267

Cited by 169 publications

(154 citation statements)

References 31 publications

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“…We used rat embryonic pancreatic epithelium grown in vitro with or without its surrounding mesenchyme. In earlier studies conducted with the same experimental system, signals from the mesenchyme activated epithelial cell proliferation and repressed endocrine cell differentiation (10). We found evidence that this repressive effect of the mesenchyme on endocrine cell differentiation required a functional mitogen-activated protein (MAP) kinase signaling pathway.…”

mentioning

confidence: 76%

Role for FGFR2IIIb-mediated signals in controlling pancreatic endocrine progenitor cell proliferation

Elghazi

Cras-Méneur

Czernichow

et al. 2002

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

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116

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mentioning

confidence: 76%

Role for FGFR2IIIb-mediated signals in controlling pancreatic endocrine progenitor cell proliferation

Elghazi

Cras-Méneur

Czernichow

et al. 2002

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

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116

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“…During early stages (E9.5), the fibroblast growth factor receptor 2b (Fgfr2b) expression is detected in the epithelium, and its high affinity ligand Fgf10 is expressed in the pancreatic mesenchyme (Hart et al, 2003;Bhushan et al, 2001;Miralles et al, 1999). FGF1 and FGF7 are also expressed in the mesenchyme throughout pancreas development.…”

Section: ''Mesenchymal-epithelial'' Crosstalk In Pancreas Morphogenesismentioning

confidence: 99%

“…FGF1 and FGF7 are also expressed in the mesenchyme throughout pancreas development. As FGF10 expression diminishes at E11.5, these FGFs might be responsible for the later role of FGF in pancreatic epithelial branching morphogenesis (Miralles et al, 1999). Transgenic mice expressing dominantnegative Fgfr2b under the inducible metallothionein promoter, or mutants that lack either Fgf10 or Fgfr2b, display pancreatic hypoplasia (Celli et al, 1998;Revest et al, 2001;Bhushan et al, 2001).…”

Section: ''Mesenchymal-epithelial'' Crosstalk In Pancreas Morphogenesismentioning

confidence: 99%

Pancreas organogenesis: From bud to plexus to gland

Pan

Wright

2011

Developmental Dynamics

524

594

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Pancreas oganogenesis comprises a coordinated and highly complex interplay of signaling events and transcriptional networks that guide a step-wise process of organ development from early bud specification all the way to the final mature organ state. Extensive research on pancreas development over the last few years, largely driven by a translational potential for pancreatic diseases (diabetes, pancreatic cancer, and so on), is markedly advancing our knowledge of these processes. It is a tenable goal that we will one day have a clear, complete picture of the transcriptional and signaling codes that control the entire organogenetic process, allowing us to apply this knowledge in a therapeutic context, by generating replacement cells in vitro, or perhaps one day to the whole organ in vivo. This review summarizes findings in the past 5 years that we feel are amongst the most significant in contributing to the deeper understanding of pancreas development. Rather than try to cover all aspects comprehensively, we have chosen to highlight interesting new concepts, and to discuss provocatively some of the more controversial findings or proposals. At the end of the review, we include a perspective section on how the whole pancreas differentiation process might be able to be unwound in a regulated fashion, or redirected, and suggest linkages to the possible reprogramming of other pancreatic cell-types in vivo, and to the optimization of the forward-directed-differentiation of human embryonic stem cells (hESC), or induced pluripotential cells (iPSC), towards mature b-cells. Developmental Dynamics 240:530-565,

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“…Pancreas development and, in particular, exocrine differentiation, are critically dependent on the presence of factors secreted from mesenchyme [29][30][31]. Follistatin and fibroblast growth factors represent some of the key mesenchymal factors that actively promote pancreatic development [32][33][34]. In addition, in the endocrine compartment of the developing pancreas, glucagon and glucagon-like peptide 1-producing alpha cells play an important role in the differentiation of early insulin-producing cells [35].…”

Section: Role Of Nestin In Epithelial-mesenchymal Transitions During mentioning

confidence: 99%

Generation of pancreatic insulin-producing cells from embryonic stem cells — ‘Proof of principle’, but questions still unanswered

2006

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Abbreviations E embryonal day EB embryoid body EMT epithelial-mesenchymal transition ES embryonic stemThe generation of insulin-producing cells from differentiating mouse embryonic stem (ES) cells was described some years ago [1], but subsequent studies could not replicate the results. Instead, using the same differentiation protocol, it was found that insulin immunoreactivity occurred as a consequence of insulin uptake from the medium [2], neuronal cells were formed [2-4], or insulin was released as an artefact from differentiated ES cells [2,3]. Functional pancreatic cells, however, were successfully generated using lineage selection strategies based on pancreas-specific promoters [5,6], by modified protocols in combination with transgene expression [7][8][9], or by addition of a phosphoinositol-3 kinase inhibitor [10]. The differentiated cells showed properties of (neonatal) beta cells, such as insulin transcripts and C-peptide/insulin co-expression, insulin-secretory granules, ion channel activity of embryonal beta cells, and normalisation of blood glucose level after transplantation into diabetic mice [5][6][7][8][9][10]. Most of the differentiation protocols required a long cultivation period, including 4-5 days of embryoid body (EB) formation, followed by 3-4 weeks of differentiation, and some protocols required genetic manipulation. Recently, a relatively short procedure of pancreatic differentiation by a three-step experimental approach was published [11]. The strategy is based on the combined treatment by activin A, all-trans-retinoic acid, and other factors such as basic fibroblast growth factor (bFGF), which induced murine ES cells to differentiate into insulin-producing cells within 2 weeks. The authors presented results on insulin transcripts, C-peptide/insulin co-expression, glucose-induced insulin release, and the normalisation of glycaemia following transplantation into diabetic mice. Neuronal vs pancreatic differentiation in vivo and of ES cells in vitroOn looking more closely at the C-peptide-positive cells differentiated according to the protocol of Shi et al. [11], it became obvious that both pancreatic and neuronal differentiation had been induced. In part, the clusters showed the typical morphology of grape-like structures, but also neuronal cell types (Fig. 1a). Immunohistochemical stainings revealed varying levels of co-expression of C-peptide, a byproduct of pro-insulin synthesis (used as a marker for insulin-producing cells), and the neuron-specific beta-III tubulin (Fig. 1b-g). Such ectoderm-derived insulin-producing (C-peptide-positive) cells have been generated from ES cells via EB formation, as well as from monolayer cultures

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Signaling through fibroblast growth factor receptor 2b plays a key role in the development of the exocrine pancreas

Abstract: The

Cited by 169 publications

References 31 publications

Role for FGFR2IIIb-mediated signals in controlling pancreatic endocrine progenitor cell proliferation

Role for FGFR2IIIb-mediated signals in controlling pancreatic endocrine progenitor cell proliferation

Pancreas organogenesis: From bud to plexus to gland

Generation of pancreatic insulin-producing cells from embryonic stem cells — ‘Proof of principle’, but questions still unanswered

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