<i>neurogenin3</i>
            is required for the development of the four endocrine cell lineages of the pancreas

Gradwohl, Gérard; Dierich, Andrée; LeMeur, Marianne; Guillemot, François

doi:10.1073/pnas.97.4.1607

Cited by 1,344 publications

(1,304 citation statements)

References 34 publications

(33 reference statements)

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“…5d,e). Taken together, these findings suggest that the pancreatic endocrine differentiation program of the biliary epithelium in Hes1 -/-mice is triggered by the ectopic expression of Neurog3, which acts as a proendocrine gene to specify cell fate 12,13 . Our results show that endodermal Hes1 controls not only endodermal endocrine differentiation 5,6 but also biliary organogenesis.…”

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confidence: 82%

Conversion of biliary system to pancreatic tissue in Hes1-deficient mice

et al. 2003

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mentioning

confidence: 82%

Conversion of biliary system to pancreatic tissue in Hes1-deficient mice

et al. 2003

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“…During embryogenesis in vivo, the same transcription factors regulate both neuroectoderm and pancreatic differentiation processes in a spatially and temporally controlled manner. During pancreatic differentiation, neurog3 mRNA has been detected in pancreatic buds as early as embryonic day (E) 9.5 [13] and the neurog3 protein has been found at E11.5 in epithelial cells of the pancreatic buds [14]. Similar expression patterns were described for Pax6 and Isl1 ( [13], for review see [15]).…”

Section: Neuronal Vs Pancreatic Differentiation In Vivo and Of Es Celmentioning

confidence: 93%

“…During pancreatic differentiation, neurog3 mRNA has been detected in pancreatic buds as early as embryonic day (E) 9.5 [13] and the neurog3 protein has been found at E11.5 in epithelial cells of the pancreatic buds [14]. Similar expression patterns were described for Pax6 and Isl1 ( [13], for review see [15]). In parallel, during neuronal and glial cell development, Isl1, Pax6, and neurog3 mRNA and proteins could be detected as early as E10.5, when neurogenesis begins ( [16,17], see Table 1).…”

Section: Neuronal Vs Pancreatic Differentiation In Vivo and Of Es Celmentioning

confidence: 93%

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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“…5). The success of this mixture is likely explained by the respective TF activities: (1) Ngn3 aids acquisition of general endocrine competence; (2) Pdx1 helps establish a stable b-cell rather than other endocrine fates; (3) MafA augments Pdx1 function, but pushes the newly generated b-cell towards achieving the final mature, functional state Ahlgren et al, 1998;Gradwohl et al, 2000;Vanhoose et al, 2008). The reported induction of b-cells was sporadic, apparently occurring directly from the acinar state without replication or movement through a prolonged dedifferentiated state.…”

Section: Genetic Manipulation-based Reprogrammingmentioning

confidence: 99%

Pancreas organogenesis: From bud to plexus to gland

Pan

Wright

2011

Developmental Dynamics

514

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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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neurogenin3 is required for the development of the four endocrine cell lineages of the pancreas

Abstract: Abbreviations: PP, pancreatic polypeptide; En, embryonic day n; bHLH, basic helix-loophelix; ES, embryonic stem; kb, kilobase; TUNEL, terminal deoxynucleotidyltransferasemediated UTP end labeling.

Cited by 1,344 publications

References 34 publications

Conversion of biliary system to pancreatic tissue in Hes1-deficient mice

Conversion of biliary system to pancreatic tissue in Hes1-deficient mice

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

Pancreas organogenesis: From bud to plexus to gland

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