<i>Fgf10</i> maintains notch activation, stimulates proliferation, and blocks differentiation of pancreatic epithelial cells

Hart, Alan; Papadopoulou, S.; Edlund, Helena

doi:10.1002/dvdy.10368

Cited by 197 publications

(171 citation statements)

References 36 publications

(62 reference statements)

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“…It is significant for the discussion here that the pancreatic progenitor population that expands in response to FGFR2IIIb ligands in vitro also displays an arrest in further differentiation (Hart et al, 2003;Norgaard et al, 2003). This arrest is reversible; upon removal of FGF7, pancreatic progenitor cells expanded by this cytokine in vitro differentiate en mass to become endocrine cells (Elghazi et al, 2002).…”

Section: Discussionmentioning

confidence: 97%

FGFR2IIIb signaling regulates thymic epithelial differentiation

Dooley

Erickson

LaRochelle

et al. 2007

Developmental Dynamics

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Heterogeneous epithelial populations comprising the thymic environment influence early and late stages of T-cell development. The processes that regulate the differentiation of thymic epithelium and that are responsible for this heterogeneity are not well understood, although mesenchymal/epithelial interactions are clearly involved. Here, we show that targeted expression by thymocytes of an fibroblast growth factor receptor-2IIIb (FGFR2IIIb) ligand, FGF10, profoundly alters the differentiation and function of thymic epithelium (TE). Reconstitution of irradiated lckFGF10 mice with normal bone marrow restores normal thymic organization and function, while wild-type mice reconstituted with lckFGF10 bone marrow recapitulates some of the thymic alterations seen in lckFGF10 mice. We also demonstrate that interference with FGFR2IIIb signaling in the thymus with a soluble FGFR2IIIb dominant-negative fusion protein leads to precocious reductions in thymic size and cellularity that resemble age-related thymic involution. These findings indicate that TE compartments are dynamically maintained and that FGF signals are involved in this process. Developmental Dynamics 236:3459 -3471, 2007.

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Section: Discussionmentioning

confidence: 97%

FGFR2IIIb signaling regulates thymic epithelial differentiation

Dooley

Erickson

LaRochelle

et al. 2007

Developmental Dynamics

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“…For example, fibroblast growth factor 10 is necessary for the proliferation of early PDX1-positive pancreatic progenitor cells (17,62) and mice deficient for this growth factor develop a highly reduced beta cell mass (17). We thus tested whether the poor endocrine development observed in the absence of glucose could be due to a lack of proliferation of early PDX1-positive pancreatic progenitor cells under such conditions.…”

Section: Discussionmentioning

confidence: 99%

Glucose Is Necessary for Embryonic Pancreatic Endocrine Cell Differentiation

Guillemain

Filhoulaud

Xavier

et al. 2007

Journal of Biological Chemistry

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Mature pancreatic cells develop during embryonic life from endodermal progenitors, and this developmental process depends on activation of a hierarchy of transcription factors. While information is available on mesodermal signals controlling pancreas development, little is known about environmental factors, such as the levels of nutrients including glucose, that may control this process. Here, we studied the effects of glucose on pancreatic cells development. We used an in vitro model where both endocrine and acinar cells develop from early pancreatic and duodenal homeobox-1 (PDX1)-positive embryonic pancreatic progenitors. We first showed that glucose does not have a major effect on global pancreatic cell proliferation, survival, and acinar cell development. On the other hand, glucose controlled both alpha and beta cell development. Specifically, the surface occupied by insulin-positive cells was 20-fold higher in pancreases cultured in presence than in absence of glucose, and this effect was dose-dependent over the range 0.5-10 mM. Glucose did not appear to control beta cell development by activating the proliferation of early progenitors or beta cells themselves but instead tightly regulated cell differentiation. Thus, glucose did not modify the pattern of expression of Neurogenin3, the earliest marker of endocrine progenitor cells, but was necessary for the expression of the transcription factor NeuroD, a direct target of Neurogenin3 known to be important for proper pancreatic endocrine cell development. We conclude that glucose interferes with the pancreatic endocrine cells development by regulating the transition between Ngn3 and upstream NeuroD.The mature mammalian pancreas contains two types of tissues: endocrine islet cells that produce hormones such as insulin (beta cells) and glucagon (alpha cells) and exocrine tissue whose acinar cells produce enzymes (e.g. amylase) that are secreted via the pancreatic ducts into the intestine. The pancreas originates from the dorsal and ventral regions of the foregut endoderm directly posterior to the stomach (1). Research conducted in the last few years has shed light on the processes controlling pancreatic endocrine-cell development. Studies of genetically engineered mice have identified a hierarchy of transcription factors regulating pancreas organogenesis and islet-cell differentiation (2, 3). The endodermal region committed to a pancreatic fate expresses the transcription factor Pancreatic and duodenal homeobox-1 (Pdx-1) (4, 5). The basic helix-loop-helix factor Neurogenin3 (Ngn3) is then expressed in epithelial pancreatic progenitor cells prior to endocrine differentiation (6). Ngn3 is necessary for pancreatic endocrine cell development, and Ngn3-deficient mice lack pancreatic endocrine cells (7). Lineage tracing experiments have also provided direct evidence that NGN3-expressing cells are islet progenitors (8). Thus, Ngn3 is a valuable marker for monitoring pancreatic endocrine-cell differentiation. NGN3 controls the expression of another member of the basic ...

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“…The canonical view of the underlying mechanism is that Notch signaling controls whether cells proliferate as progenitors or differentiate, via a ''suppressive maintenance'' mechanism (Norgaard et al, 2003;Hart et al, 2003). Later, Notch signaling is a key regulator of binary cell fate decisions in endocrine specification, where it may use the classical ''lateral inhibition'' mechanism (see Endocrine Specification section).…”

Section: Notch Signaling In Early Pancreatic Progenitor Developmentmentioning

confidence: 99%

“…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%

“…Furthermore, Pdx1 promoter-driven FGF10 mis-expression in the epithelium led to increased proliferation of pancreatic progenitors and a greatly reduced rate of differentiation of endocrine and exocrine cells. This effect of FGF10 again relates to the ''suppressive maintenance'' role of Notch in the pancreatic progenitors: excess FGF10 signaling leads to sustained Notch activation and promotes proliferation at the progenitor state (Norgaard et al, 2003;Hart et al, 2003).…”

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

confidence: 99%

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Pancreas organogenesis: From bud to plexus to gland

Pan

Wright

2011

Developmental Dynamics

525

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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Fgf10 maintains notch activation, stimulates proliferation, and blocks differentiation of pancreatic epithelial cells

Cited by 197 publications

References 36 publications

FGFR2IIIb signaling regulates thymic epithelial differentiation

FGFR2IIIb signaling regulates thymic epithelial differentiation

Glucose Is Necessary for Embryonic Pancreatic Endocrine Cell Differentiation

Pancreas organogenesis: From bud to plexus to gland

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