Homeobox gene Nkx6.1 lies downstream of Nkx2.2 in the major pathway of β-cell formation in the pancreas

Hormone Research Institute, University of California San Francisco, San Francisco, CA 94143-0534, USA.
Development (Impact Factor: 6.46). 01/2001; 127(24):5533-40.
Source: PubMed


Most insulin-producing beta-cells in the fetal mouse pancreas arise during the secondary transition, a wave of differentiation starting at embryonic day 13. Here, we show that disruption of homeobox gene Nkx6.1 in mice leads to loss of beta-cell precursors and blocks beta-cell neogenesis specifically during the secondary transition. In contrast, islet development in Nkx6. 1/Nkx2.2 double mutant embryos is identical to Nkx2.2 single mutant islet development: beta-cell precursors survive but fail to differentiate into beta-cells throughout development. Together, these experiments reveal two independently controlled pathways for beta-cell differentiation, and place Nkx6.1 downstream of Nkx2.2 in the major pathway of beta-cell differentiation.

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Available from: David W Scheel, Sep 29, 2015
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    • "Development of the ductal/endocrine lineages from MPCs is associated with loss of Ptf1a and maintenance of Nkx6-1 expression, whereas the downregulation of Nkx6-1 and sustained expression of Ptf1a are required for specification of the exocrine lineage (Schaffer et al., 2010). Expression of Nkx6-1 is required for development of the beta cell lineage from endocrine progenitors (Sander et al., 2000). "
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    ABSTRACT: Human pluripotent stem cells (hPSCs) represent a renewable source of pancreatic beta cells for both basic research and therapeutic applications. Given this outstanding potential, significant efforts have been made to identify the signaling pathways that regulate pancreatic development in hPSC differentiation cultures. In this study, we demonstrate that the combination of epidermal growth factor (EGF) and nicotinamide signaling induces the generation of NKX6-1(+) progenitors from all hPSC lines tested. Furthermore, we show that the size of the NKX6-1(+) population is regulated by the duration of treatment with retinoic acid, fibroblast growth factor 10 (FGF10), and inhibitors of bone morphogenetic protein (BMP) and hedgehog signaling pathways. When transplanted into NOD scid gamma (NSG) recipients, these progenitors differentiate to give rise to exocrine and endocrine cells, including monohormonal insulin(+) cells. Together, these findings provide an efficient and reproducible strategy for generating highly enriched populations of hPSC-derived beta cell progenitors for studies aimed at further characterizing their developmental potential in vivo and deciphering the pathways that regulate their maturation in vitro. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Stem Cell Reports 04/2015; 7(4). DOI:10.1016/j.stemcr.2015.02.017 · 5.37 Impact Factor
    • "A pancreatic progenitor cell is defined by coexpression of the transcription factors Pdx1, Nkx6.1, Nkx2.2, Ptf1a, and Sox9 in the embryonic pancreas epithelium, and the lack of one of these transcription factors can result in abnormal beta cell development (Gittes, 2009). For instance, pancreatic cells in homozygous Nkx6.1 mutant mice develop into NGN3-positive endocrine progenitors and insulin and glucagon co-expressing cells, but fail to form monohormonal insulin-expressing beta cells at embryonic day 18.5 (Sander et al, 2000). During mouse embryonic development, two waves of Ngn3 expression, initiated before and after Nkx6.1 expression, have a vastly different outcome on the phenotype of endocrine cells. "
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    ABSTRACT: Bjarki Johannesson1, Lina Sui2, Donald O Freytes1, Remi J Creusot3 and Dieter Egli*,1,21The New York Stem Cell Foundation Research Institute, New York, NY, USA2Naomi Berrie Diabetes Center & Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY, USA3Columbia Center for Translational Immunology, Department of Medicine and Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA↵*Corresponding author. Tel: +1 212 851 4890; E‐mail: de2220{at} Abstract The discovery of insulin more than 90 years ago introduced a life‐saving treatment for patients with type 1 diabetes, and since then, significant progress has been made in clinical care for all forms of diabetes. However, no method of insulin delivery matches the ability of the human pancreas to reliably and automatically maintain glucose levels within a tight range. Transplantation of human islets or of an intact pancreas can in principle cure diabetes, but this approach is generally reserved for cases with simultaneous transplantation of a kidney, where immunosuppression is already a requirement. Recent advances in cell reprogramming and beta cell differentiation now allow the generation of personalized stem cells, providing an unlimited source of beta cells for research and for developing autologous cell therapies. In this review, we will discuss the utility of stem cell‐derived beta cells to investigate the mechanisms of beta cell failure in diabetes, and the challenges to develop beta cell replacement therapies. These challenges include appropriate quality controls of the cells being used, the ability to generate beta cell grafts of stable cellular composition, and in the case of type 1 diabetes, protecting implanted cells from autoimmune destruction without compromising other aspects of the immune system or the functionality of the graft. Such novel treatments will need to match or exceed the relative safety and efficacy of available care for diabetes. beta cellscell replacement therapystem cellstype 1 diabetesReceived November 27, 2014.Revision received January 13, 2015.Accepted January 22, 2015.© 2015 The Authors
    The EMBO Journal 01/2015; · 10.43 Impact Factor
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    • "The lung biomarker NAPSA is a well characterized proteinase expressed in type II pneumocytes [65] [66] [67], whose expression has high sensitivity and specificity for distinguishing primary lung adenocarcinoma from metastatic pulmonary lesions from other primaries [67]. The pancreas biomarker NKX6-1 is a transcriptional regulator that has been shown to play an important role in beta cell differentiation during pancreatic development [68] [69] [70] [71]. "
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    Neoplasia (New York, N.Y.) 11/2014; 16(11). DOI:10.1016/j.neo.2014.09.007 · 4.25 Impact Factor
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