Neurogenin3: A master regulator of pancreatic islet differentiation and regeneration

Rukstalis, J. Michael; Habener, Joel F.

doi:10.4161/isl.1.3.9877

Cited by 119 publications

(130 citation statements)

References 71 publications

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“…This would also raise the possibility that, being a bHLH factor, Hes3 may interfere with the actions of other bHLH factors of importance to pancreatic development and function such as Ngn3 (5,73,87,88). In another parallel between brain and pancreas, Ngn3 has important functions in the development of the brain (including hippocampal and hypothalamic neurons and glial progenitors), islet cell specification, and b-cell regeneration (18,(89)(90)(91).…”

Section: Notch Signaling In Neural Developmentmentioning

confidence: 99%

Endocrine Pancreas Development and Regeneration: Noncanonical Ideas From Neural Stem Cell Biology

et al. 2016

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Loss of insulin-producing pancreatic islet β-cells is a hallmark of type 1 diabetes. Several experimental paradigms demonstrate that these cells can, in principle, be regenerated from multiple endogenous sources using signaling pathways that are also used during pancreas development. A thorough understanding of these pathways will provide improved opportunities for therapeutic intervention. It is now appreciated that signaling pathways should not be seen as “on” or “off” but that the degree of activity may result in wildly different cellular outcomes. In addition to the degree of operation of a signaling pathway, noncanonical branches also play important roles. Thus, a pathway, once considered as “off” or “low” may actually be highly operational but may be using noncanonical branches. Such branches are only now revealing themselves as new tools to assay them are being generated. A formidable source of noncanonical signal transduction concepts is neural stem cells because these cells appear to have acquired unusual signaling interpretations to allow them to maintain their unique dual properties (self-renewal and multipotency). We discuss how such findings from the neural field can provide a blueprint for the identification of new molecular mechanisms regulating pancreatic biology, with a focus on Notch, Hes/Hey, and hedgehog pathways.

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Section: Notch Signaling In Neural Developmentmentioning

confidence: 99%

Endocrine Pancreas Development and Regeneration: Noncanonical Ideas From Neural Stem Cell Biology

et al. 2016

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“…During the secondary transition (E13.5-E16.5), the pan- creas undergoes rapid growth and branching. A second wave of NGN3-positive cells occurs, which differentiates into a second wave of endocrine cells [44]. NGN3-positive cells that appear towards the end of the first wave (E10.5), and during the second wave increasingly acquire the competence to generate beta-cells and PP cells, in addition to alpha-cells.…”

Section: Secondary Transitionmentioning

confidence: 99%

“…Its expression defines the endocrine niche within the PE (reviewed by Rukstalis and Habener [44]), concluded by the observation that NGN3-deficient mice completely lack endocrine cells [45]. NGN3 induces the expression of several transcription factors that locate to the islet cells within the pancreas.…”

Section: Primary Transitionmentioning

confidence: 99%

Maturation of Stem Cell-Derived Beta-cells Guided by the Expression of Urocortin 3

Meulen¹,

Huising²

2014

Rev Diabet Stud

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■ AbstractType 1 diabetes (T1D) is a devastating disease precipitated by an autoimmune response directed at the insulinproducing beta-cells of the pancreas for which no cure exists. Stem cell-derived beta-cells show great promise for a cure as they have the potential to supply unlimited numbers of cells that could be derived from a patient's own cells, thus eliminating the need for immunosuppression. Current in vitro protocols for the differentiation of stem cell-derived beta-cells can successfully generate pancreatic endoderm cells. In diabetic rodents, such cells can differentiate further along the beta-cell lineage until they are eventually capable of restoring normoglycemia. While these observations demonstrate that stem cell-derived pancreatic endoderm has the potential to differentiate into mature, glucose-responsive beta-cells, the signals that direct differentiation and maturation from pancreatic endoderm onwards remain poorly understood. In this review, we analyze the sequence of events that culminates in the formation of beta-cells during embryonic development, and we summarize how current protocols to generate beta-cells have sought to capitalize on this ontogenic template. We place particular emphasis on the current challenges and opportunities which occur in the later stages of beta-cell differentiation and maturation of transplantable stem cell-derived beta-cells. Another focus is on the question how the use of recently identified maturation markers such as urocortin 3 can be instrumental in guiding these efforts.

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“…SOX4 regulates endocrine cell differentiation downstream of NEUROG3 SOX4 expression is maintained at high levels in both mouse and human islets (ESM Figs 2 and 5); however, NEUROG3 expression is not [44]. In order to test if the (Fig.…”

Section: Sox4 Is Dynamically Expressed During Mouse Pancreas Formatiomentioning

confidence: 99%

SOX4 cooperates with neurogenin 3 to regulate endocrine pancreas formation in mouse models

Krentz

Tan

et al. 2015

Diabetologia

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Aims/hypothesis The sex-determining region Y (SRY)-related high mobility group (HMG) box (SOX) family of transcription factors is essential for normal organismal development. Despite the longstanding knowledge that many SOX family members are expressed during pancreas development, a role for many of these factors in the establishment of insulinproducing beta cell fate remains to be determined. The aim of this study is to elucidate the role of SOX4 during beta cell development. Methods We used pancreas and endocrine progenitor mouse knockouts of Sox4 to uncover the roles of SOX4 during pancreas development. Lineage tracing and in vitro models were used to determine how SOX4 regulates beta cell formation and understand the fate of Sox4-null endocrine lineage cells. Results This study demonstrates a progenitor cellautonomous role for SOX4 in regulating the genesis of beta cells and shows that it is required at multiple stages of the process. SOX4 deletion in the multipotent pancreatic progenitors resulted in impaired endocrine progenitor cell differentiation. Deletion of SOX4 later in the Neurog3-expressing cells also caused reductions in beta cells. Lineage studies showed loss of Sox4 in endocrine progenitors resulted in a block in terminal islet cell differentiation that was attributed to reduction in the production of key beta cell specification factors. Conclusions/interpretation These results demonstrate that SOX4 is essential for normal endocrine pancreas development both concomitant with, and downstream of, the endocrine fate decision. In conclusion, these studies position Sox4 temporally in the endocrine differentiation programme and provide a new target for improving in vitro differentiation of glucoseresponsive pancreatic beta cells.

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Neurogenin3: A master regulator of pancreatic islet differentiation and regeneration

Cited by 119 publications

References 71 publications

Endocrine Pancreas Development and Regeneration: Noncanonical Ideas From Neural Stem Cell Biology

Endocrine Pancreas Development and Regeneration: Noncanonical Ideas From Neural Stem Cell Biology

Maturation of Stem Cell-Derived Beta-cells Guided by the Expression of Urocortin 3

SOX4 cooperates with neurogenin 3 to regulate endocrine pancreas formation in mouse models

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