Stem Cells
- Epithelial regeneration and cancer: news from the Src front
Src family kinases (SFKs) have long been implicated in tumorigenesis, but the exact requirement for individual kinase members, and their specific spatially and temporally defined roles in the maintenance of epithelial homeostasis remained unclear. A study by Cordero et al (2014) now combines the strengths of Drosophila and mouse models for intestinal epithelial regeneration to characterize the role of individual SFKs in epithelial stem cells, tissue regeneration, and tumorigenesis.
See also: JB Cordero et al (July 2014)
The experimental power of Drosophila and mouse models enables the functional dissection of distinct Src family kinase family members in the homeostasis of intestinal stem cells.
- © 2014 The Authors
- Wnt meets Warburg: another piece in the puzzle?
- Craig B Thompson (craig{at}mskcc.org) 1
One of the most common abnormalities of cancer cells is their predilection to engage in a high rate of glycolysis despite the continued availability of oxygen. First described by Otto Warburg, this phenomenon of aerobic glycolysis (or the Warburg effect) has recently been proposed to result from cancer‐associated alterations in signal transduction pathways. In this issue of The EMBO Journal, Pate et al provide further support for this hypothesis by demonstrating that Wnt signaling plays an important role in establishing aerobic glycolysis as a mechanism to support in vivo cancer cell proliferation.
See also: KT Pate et al (July 2014)
The discovery of PDK1 and the lactate transporter MCT‐1 as direct Wnt targets functionally links Wnt signaling to the aerobic switch and critical angiogenic responses in tumor cells and normal stem cells.
- © 2014 The Author
- Specific ablation of Nampt in adult neural stem cells recapitulates their functional defects during aging
- ↵*Corresponding author. Tel: +1 314 362 7228; Fax: +1 314 362 7058; E‐mail: imaishin{at}wustl.edu
NAD+ and the NAD+ biosynthetic enzyme Nampt decline in the aging hippocampus. Nampt ablation in adult neural stem cells in vivo reduces cell numbers, proliferation, and oligodendrogenesis. Decreases in the stem cell pool are reversed by enhancing hippocampal NAD+.
Synopsis
Levels of NAD+ and the NAD+ biosynthetic enzyme Nampt decline in the hippocampus during aging. Nampt ablation in adult neural stem/progenitor cells reduces self‐renewal, proliferation, and oligodendrogenesis. Age‐associated decreases in the stem cell pool are reversed by the administration of nicotinamide mononucleotide, a key NAD+ intermediate.
Nampt is expressed in adult neural/progenitor stem cells and is the main source of their NAD+ levels.
Loss of Nampt reduces proliferation by stalling progression of the neural stem/progenitor cell cycle at G0/G1.
The NAD+‐dependent sirtuins Sirt1 and Sirt2 redundantly mediate neural stem/progenitor cell fate decisions into oligodendrocytes.
Loss of Nampt reduces neural stem/progenitor cell‐derived oligodendrocyte regeneration after cuprizone‐induced demyelination.
The EMBO Journal (2014) 33: 1321–1340
- Received September 17, 2013.
- Revision received March 27, 2014.
- Accepted March 29, 2014.
- © 2014 The Authors
- MiR‐135b is a direct PAX6 target and specifies human neuroectoderm by inhibiting TGF‐β/BMP signaling
- Akshay Bhinge1,
- Jeremie Poschmann2,†,
- Seema C Namboori1,†,
- Xianfeng Tian1,†,
- Sharon Jia Hui Loh1,
- Anna Traczyk1,
- Shyam Prabhakar2 and
- Lawrence W Stanton*,1,3,4
- 1Stem Cell and Developmental Biology, Genome Institute of Singapore, Singapore City, Singapore
- 2Computational and Systems Biology, Genome Institute of Singapore, Singapore City, Singapore
- 3Department of Biological Sciences, National University of Singapore, Singapore City, Singapore
- 4School of Biological Sciences Nanyang Technological University, Singapore City, Singapore
- ↵*Corresponding author. Tel: +65 6478 8006; Fax: +65 6478 9051; E‐mail: stantonl{at}gis.a-star.edu.sg
-
↵† These authors contributed equally to this work.
A genome‐wide association study on the neural inducer Pax6 identifies miR‐135b as a novel Pax6 target that promotes neuroectoderm induction by antagonizing BMP and Activin/Nodal signals.
Synopsis
A genome‐wide association study on the neural inducer Pax6 identifies miR‐135b as a novel Pax6 target that promotes neuroectoderm (NE) induction by antagonizing BMP and Activin/Nodal signals.
Genome‐wide study to identify downstream targets of the master transcriptional regulator Pax6 in human NE;
Reports direct Pax6 localization to promoters of several TFs known to govern neural differentiation;
Reveals Pax6 regulation of microRNAs involved in neural specification;
Identifies Pax6 regulation of miR‐135b to inhibit TGF‐β and BMP signals and thus facilitate NE specification.
The EMBO Journal (2014) 33: 1271–1283
- Received October 22, 2013.
- Revision received April 3, 2014.
- Accepted April 3, 2014.
- © 2014 The Authors
- The ER under rapid fire
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease leading to selective death of upper and lower motoneurons. Clinically, the ALS syndrome is linked to pathogenic mutations in superoxide dismutase 1 (SOD1), though actual molecular mechanisms remain ill understood. Two papers recently published in Cell Stem Cell and Cell Reports employ syngenic, iPSC‐derived cell lines of one of the most severe SOD1 mutations to report mitochondrial and ER stress as causal for perturbed electrical activity in ALS neurons (Kiskinis et al, 2014; Wainger et al, 2014).
See also: E Kiskinis et al (April 2014) &
BJ Wainger et al (April 2014)
Combining the iPSC technology with genome‐editing/genome‐sequencing and cell‐biological tools offers intriguing novel insights into the molecular aberrations that cause fatal motoneuron death in ALS patients.
- © 2014 The Authors
- c‐Src drives intestinal regeneration and transformation
- Julia B Cordero15,
- Rachel A Ridgway1,
- Nicola Valeri2,
- Colin Nixon1,
- Margaret C Frame4,
- William J Muller3,
- Marcos Vidal1 and
- Owen J Sansom*,1
- 1The Beatson Institute for Cancer Research, Bearsden Glasgow, UK
- 2Institute of Cancer Research, Sutton London, UK
- 3Goodman Cancer Research Center McGill University, Montreal, QC, Canada
- 4Edinburgh Cancer Research Centre Institute of Genetics & Molecular Medicine University of Edinburgh, Edinburgh, UK
- 5Wolfson Wohl Cancer Research Centre Institute of Cancer Sciences University of Glasgow, Garscube Estate, Switchback Road, Bearsden Glasgow, UK
- ↵*Corresponding author: Tel: +44 141 330 3953; E‐mail: o.sansom{at}beatson.gla.ac.uk
These comprehensive, cross‐organismal experiments determine the evolutionary conservation and central position of Src family kinases in intestinal stem cell renewal, tumour formation and proliferative tissue regeneration.
Synopsis
These comprehensive, cross‐organismal experiments determine the evolutionary conservation and central position of Src family kinases in intestinal stem cell renewal, tumour formation and proliferative tissue regeneration.
Src is activated in stem/progenitor cells in response to damage and loss of Apc in the intestine.
Src is required for intestinal regeneration and Apc loss‐driven tumourigenesis.
Src family kinases are required for homeostatic self‐renewal of the intestinal epithelium.
Src requirement in intestine physiology and pathology is conserved from Drosophila to mammals.
The EMBO Journal (2014) 33: 1474–1491
- Received November 19, 2013.
- Revision received March 11, 2014.
- Accepted April 8, 2014.
- © 2014 The Authors. Published under the terms of the CC BY NC ND 4.0 license
This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs 4.0 License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
- The uncommon roles of common gene regulatory factors in the genomes of differentiating cells
- Eric H Davidson (davidson{at}caltech.edu) 1
Viewed through the lens of comparative regulatory mechanisms in developmental processes, the article of Calero‐Nieto et al (2014, this issue) is of particular interest. This work uncovers the causal combinatorial subtleties of the distinct enhancer occupancy profiles displayed by ten different transcription factors, which are expressed in common in two hematopoietic cell types, a stem cell‐like precursor and primary mast cells.
See also: FJ Calero-Nieto et al (June 2014)
The integration of various ‘systems‐level’ analyses reveals functional, rather than opportunistic, promoter binding of a common set of hematopoietic transcription factors to govern tissue‐specific gene expression.
- © 2014 The Author
- Key regulators control distinct transcriptional programmes in blood progenitor and mast cells
- Fernando J Calero‐Nieto*,1,†,
- Felicia S Ng1,†,
- Nicola K Wilson1,
- Rebecca Hannah1,
- Victoria Moignard1,
- Ana I Leal‐Cervantes1,
- Isabel Jimenez‐Madrid1,
- Evangelia Diamanti1,
- Lorenz Wernisch2 and
- Berthold Göttgens*,1
- 1Department of Haematology, Wellcome Trust and MRC Cambridge Stem Cell Institute, Cambridge Institute for Medical Research, Cambridge University, Cambridge, UK
- 2MRC Biostatistics Unit, Institute of Public Health, Cambridge, UK
- ↵*
Corresponding author. Tel: +44 1223 336822; Fax: +44 1223 762670; E‐mail: fjc28{at}cam.ac.uk
Corresponding author. Tel: +44 1223 336829; Fax: +44 1223 762670; E‐mail: bg200{at}cam.ac.uk
-
↵† These authors contributed equally to this work.
Comparative profiling of ten key haematopoietic transcription factors in blood progenitors versus mast cells demonstrates tissue‐specific binding profiles that functionally determine cellular identify.
Synopsis
Comparative profiling of ten key haematopoietic transcription factors in blood progenitors versus mast cells demonstrates tissue‐specific binding profiles that functionally determine cellular identify.
Genome‐wide binding profiles for 10 TFs in blood progenitors and mast cells
Differential binding of shared TFs is predictive of differential gene expression.
Cell type‐specific TFs may reorganise global binding profiles of shared TFs.
Cell type‐specific binding of shared TFs is not predominantly opportunistic.
The EMBO Journal (2014) 33: 1212–1226
- Received September 6, 2013.
- Revision received February 27, 2014.
- Accepted March 20, 2014.
- © 2014 The Authors. Published under the terms of the CC BY license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Miro1: New wheels for transferring mitochondria
Mesenchymal stem cells (MSC) are capable of protecting cells harboring mitochondrial damage. This protection is associated with the transfer of mitochondria through tunneling nanotubes (TNT) from MSC to the injured cells. In this issue of The EMBO Journal, the group of Anurag Agrawal shows that mitochondrial transfer is dependent on the levels of Miro1, a mitochondrial Rho‐GTPase that regulates intercellular mitochondrial movement. Miro1 is the first protein shown to accelerate mitochondrial transfer. Amplifying the mitochondrial transfer phenomenon may allow for the study of the mechanisms that regulate it and contribute to our understanding of its role in disease and aging.
See also: T Ahmad et al (May 2014)
The mitochondrial Rho‐GTPase Miro1 regulates intercellular mitochondrial transfer between mesenchymal stem cells and epithelial cells in different models of epithelial lung injury.
- © 2014 The Authors
- miR379–410 cluster miRNAs regulate neurogenesis and neuronal migration by fine‐tuning N‐cadherin
- 1Department of Molecular Embryology, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
- 2University of Freiburg Faculty of Biology, Freiburg, Germany
- 3Department of Biomedicine, University of Basel, Basel, Switzerland
- 4Institute of Human Genetics University Medical Centre of the Johannes Gutenberg University, Mainz, Germany
- ↵*Corresponding author. Tel: +49 6131 179684; Fax: +49 6131 175690; E‐mail: jewinter{at}uni-mainz.de
Members of the miR379–410 miRNA cluster control the proliferation and differentiation of radial glial cells (RGCs) and the migration of cortical neurons by reducing N‐cadherin levels in the developing neocortex.
Synopsis
Members of the miR379–410 miRNA cluster control the proliferation and differentiation of radial glial cells (RGCs) and the migration of cortical neurons by reducing N‐cadherin levels in the developing neocortex.
miR369‐3p, miR496 and miR543 are expressed in the mouse developing neocortex.
miR369‐3p, miR496 and miR543 regulate the proliferation and differentiation of RGCs into cortical neurons.
miR369‐3p, miR496 and miR543 control cortical neuron migration.
miR369‐3p, miR496 and miR543 exert their effects via reduction of N‐cadherin expression in vitro and in vivo.
EMBO J (2014) 33, 906–920
- Received August 13, 2013.
- Revision received January 29, 2014.
- Accepted January 29, 2014.
- © 2014 The Authors
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