| 1. |
- Sahara, Makoto, et al.
(author)
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Population and single-cell analysis of human cardiogenesis reveals unique LGR5 ventricular progenitors in embryonic outflow tract
- 2019
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In: Developmental Cell. - Stockholm : Karolinska Institutet, Dept of Cell and Molecular Biology. - 1534-5807 .- 1878-1551.
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Journal article (peer-reviewed)abstract
- The morphogenetic process of mammalian cardiac development is complex and highly regulated spatiotemporally by multipotent cardiac stem/progenitor cells (CPCs). Mouse studies have been informative for understanding mammalian cardiogenesis; however, similar insights have been poorly established in humans. Here, we report comprehensive gene expression profiles of human cardiac derivatives from multipotent CPCs to intermediates and mature cardiac cells by population and single-cell RNA-seq using human embryonic stem cell-derived and embryonic/fetal heart-derived cardiac cells micro-dissected from specific heart compartments. Importantly, we discover a uniquely human subset of cono-ventricular region-specific CPCs, marked by LGR5. At 4 to 5 weeks of fetal age, the LGR5+ population appears to emerge specifically in the proximal outflow tract of human embryonic hearts and thereafter promotes cardiac development and alignment through expansion of the ISL1+TNNT2+ intermediates. The current study contributes to a deeper understanding of human cardiogenesis, which may uncover the putative origins of certain human congenital cardiac malformations.
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| 2. |
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| 3. |
- Wagner, Ines, et al.
(author)
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Serum proteases potentiate BMP-induced cell cycle re-entry of dedifferentiating muscle cells during newt limb regeneration
- 2017
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In: Developmental Cell. - Stockholm : Karolinska Institutet, Dept of Cell and Molecular Biology. - 1534-5807 .- 1878-1551.
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Journal article (peer-reviewed)abstract
- Limb amputation in the newt induces myofibers to dedifferentiate and re-enter the cell cycle to generate proliferative myogenic precursors in the regeneration blastema. Here we show that bone morphogenetic proteins (BMPs) and mature BMPs that have been further cleaved by serum proteases induce cell cycle entry by dedifferentiating newt muscle cells. Protease-activated BMP4/7 heterodimers that are present in serum strongly induced myotube cell cycle re-entry with protease cleavage yielding a 30-fold potency increase of BMP4/7 compared with canonical BMP4/7. Inhibition of BMP signaling via muscle-specific dominant-negative receptor expression reduced cell cycle entry in vitro and in vivo. In vivo inhibition of serine protease activity depressed cell cycle re-entry, which in turn was rescued by cleaved-mimic BMP. This work identifies a mechanism of BMP activation that generates blastema cells from differentiated muscle.
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| 4. |
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| 5. |
- Ando, Koji, et al.
(author)
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KCNJ8/ABCC9-containing K-ATP channel modulates brain vascular smooth muscle development and neurovascular coupling
- 2022
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In: Developmental Cell. - : Elsevier. - 1534-5807 .- 1878-1551. ; 57:11, s. 1383-1399.e7
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Journal article (peer-reviewed)abstract
- Loss- or gain-of-function mutations in ATP-sensitive potassium channel (K-ATP)-encoding genes, KCNJ8 and ABCC9, cause human central nervous system disorders with unknown pathogenesis. Here, using mice, zebrafish, and cell culture models, we investigated cellular and molecular causes of brain dysfunctions derived from altered K-ATP channel function. We show that genetic/chemical inhibition or activation of KCNJ8/ABCC9-containing K-ATP channel function leads to brain-selective suppression or promotion of arterial/arteriolar vascular smooth muscle cell (VSMC) differentiation, respectively. We further show that brain VSMCs develop from KCNJ8/ABCC9-containing K-ATP channel-expressing mural cell progenitor and that K-ATP channel cell autonomously regulates VSMC differentiation through modulation of intracellular Ca2+ oscillation via voltage-dependent calcium channels. Consistent with defective VSMC development, Kcnj8 knockout mice showed deficiency in vasoconstrictive capacity and neuronal-evoked vasodilation leading to local hyperemia. Our results demonstrate a role for KCNJ8/ABCC9-containing K-ATP channels in the differentiation of brain VSMC, which in turn is necessary for fine-tuning of cerebral blood flow.
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| 6. |
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| 7. |
- Baek, Sungmin, et al.
(author)
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The Alternative Splicing Regulator Nova2 Constrains Vascular Erk Signaling to Limit Specification of the Lymphatic Lineage
- 2019
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In: Developmental Cell. - : CELL PRESS. - 1534-5807 .- 1878-1551. ; 49:2, s. 279-292
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Journal article (peer-reviewed)abstract
- The correct assignment of cell fate within fields of multipotent progenitors is essential for accurate tissue diversification. The first lymphatic vessels arise from pre-existing veins after venous endothelial cells become specified as lymphatic progenitors. Prox1 specifies lymphatic fate and labels these progenitors; however, the mechanisms restricting Prox1 expression and limiting the progenitor pool remain unknown. We identified a zebrafish mutant that displayed premature, expanded, and prolonged lymphatic specification. The gene responsible encodes the regulator of alternative splicing, Nova2. In zebrafish and human endothelial cells, Nova2 selectively regulates pre-mRNA splicing for components of signaling pathways and phosphoproteins. Nova2-deficient endothelial cells display increased Mapk/Erk signaling, and Prox1 expression is dynamically controlled by Erk signaling. We identify a mechanism whereby Nova2-regulated splicing constrains Erk signaling, thus limiting lymphatic progenitor cell specification. This identifies the capacity of a factor that tunes mRNA splicing to control assignment of cell fate during vascular differentiation.
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| 8. |
- Bahrampour, Shahrzad, et al.
(author)
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Neural Lineage Progression Controlled by a Temporal Proliferation Program.
- 2017
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In: Developmental Cell. - : Cell Press. - 1534-5807 .- 1878-1551. ; 43:3, s. 332-348
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Journal article (peer-reviewed)abstract
- Great progress has been made in identifying transcriptional programs that establish stem cell identity. In contrast, we have limited insight into how these programs are down-graded in a timely manner to halt proliferation and allow for cellular differentiation. Drosophila embryonic neuroblasts undergo such a temporal progression, initially dividing to bud off daughters that divide once (type I), then switching to generating non-dividing daughters (type 0), and finally exiting the cell cycle. We identify six early transcription factors that drive neuroblast and type I daughter proliferation. Early factors are gradually replaced by three late factors, acting to trigger the type I→0 daughter proliferation switch and eventually to stop neuroblasts. Early and late factors regulate each other and four key cell-cycle genes, providing a logical genetic pathway for these transitions. The identification of this extensive driver-stopper temporal program controlling neuroblast lineage progression may have implications for studies in many other systems.less thanbr /greater than (Copyright © 2017 Elsevier Inc. All rights reserved.)
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| 9. |
- Baral, Anirban, et al.
(author)
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External Mechanical Cues Reveal a Katanin-Independent Mechanism behind Auxin-Mediated Tissue Bending in Plants
- 2021
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In: Developmental Cell. - : Elsevier BV. - 1534-5807 .- 1878-1551. ; 56, s. 67-
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Journal article (peer-reviewed)abstract
- Tissue folding is a central building block of plant and animal morphogenesis. In dicotyledonous plants, hypocotyl folds to form hooks after seedling germination that protects their aerial stem cell niche during emergence from soil. Auxin response factors and auxin transport are reported to play a key role in this process. Here, we show that the microtubule-severing enzyme katanin contributes to hook formation. However, by exposing hypocotyls to external mechanical cues mimicking the natural soil environment, we reveal that auxin response factors ARF7/ARF19, auxin influx carriers, and katanin are dispensable for apical hook formation, indicating that these factors primarily play the role of catalyzers of tissue bending in the absence of external mechanical cues. Instead, our results reveal the key roles of the non-canonical TMK-mediated auxin pathway, PIN efflux carriers, and cellulose microfibrils as components of the core pathway behind hook formation in the presence or absence of external mechanical cues.
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| 10. |
- Baumgardt, Magnus, et al.
(author)
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Global Programmed Switch in Neural Daughter Cell Proliferation Mode Triggered by a Temporal Gene Cascade
- 2014
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In: Developmental Cell. - : Elsevier (Cell Press). - 1534-5807 .- 1878-1551. ; 30:2, s. 192-208
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Journal article (peer-reviewed)abstract
- During central nervous system (CNS) development, progenitors typically divide asymmetrically, renewing themselves while budding off daughter cells with more limited proliferative potential. Variation in daughter cell proliferation has a profound impact on CNS development and evolution, but the underlying mechanisms remain poorly understood. We find that Drosophila embryonic neural progenitors (neuroblasts) undergo a programmed daughter proliferation mode switch, from generating daughters that divide once (type I) to generating neurons directly (type 0). This typelgreater than0 switch is triggered by activation of Dacapo (mammalian p21(CIP1)/p27(KIP1)/p57(Kip2)) expression in neuroblasts. In the thoracic region, Dacapo expression is activated by the temporal cascade (castor) and the Hox gene Antennapedia. In addition, castor, Antennapedia, and the late temporal gene grainyhead act combinatorially to control the precise timing of neuroblast cell-cycle exit by repressing Cyclin E and E2f. This reveals a logical principle underlying progenitor and daughter cell proliferation control in the Drosophila CNS.
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| 11. |
- Bazigou, Eleni, et al.
(author)
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Integrin-alpha9 is required for fibronectin matrix assembly during lymphatic valve morphogenesis.
- 2009
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In: Developmental Cell. - : Elsevier BV. - 1534-5807 .- 1878-1551. ; 17:2
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Journal article (peer-reviewed)abstract
- Dysfunction of lymphatic valves underlies human lymphedema, yet the process of valve morphogenesis is poorly understood. Here, we show that during embryogenesis, lymphatic valve leaflet formation is initiated by upregulation of integrin-alpha9 expression and deposition of its ligand fibronectin-EIIIA (FN-EIIIA) in the extracellular matrix. Endothelial cell-specific deletion of Itga9 (encoding integrin-alpha9) in mouse embryos results in the development of rudimentary valve leaflets characterized by disorganized FN matrix, short cusps, and retrograde lymphatic flow. Similar morphological and functional defects are observed in mice lacking the EIIIA domain of FN. Mechanistically, we demonstrate that in primary human lymphatic endothelial cells, the integrin-alpha9-EIIIA interaction directly regulates FN fibril assembly, which is essential for the formation of the extracellular matrix core of valve leaflets. Our findings reveal an important role for integrin-alpha9 signaling during lymphatic valve morphogenesis and implicate it as a candidate gene for primary lymphedema caused by valve defects.
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| 12. |
- Benton, Jeanne, et al.
(author)
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Cells from the Immune System Generate Adult-Born Neurons in Crayfish
- 2014
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In: Developmental Cell. - : Cell Press. - 1534-5807 .- 1878-1551. ; 30:3, s. 322-333
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Journal article (peer-reviewed)abstract
- Neurogenesis is an ongoing process in the brains of adult decapod crustaceans. However, the first-generation precursors that produce adult-born neurons, which reside in a neurogenic niche, are not self-renewing in crayfish and must be replenished. The source of these neuronal precursors is unknown. Here, we report that adult-born neurons in crayfish can be derived from hemocytes. Following adoptive transfer of 5-ethynyl-2′-deoxyuridine (EdU)-labeled hemocytes, labeled cells populate the neurogenic niche containing the first-generation neuronal precursors. Seven weeks after adoptive transfer, EdU-labeled cells are located in brain clusters 9 and 10 (where adult-born neurons differentiate) and express appropriate neurotransmitters. Moreover, the number of cells composing the neurogenic niche in crayfish is tightly correlated with total hemocyte counts (THCs) and can be manipulated by raising or lowering THC. These studies identify hemocytes as a source of adult-born neurons in crayfish and demonstrate that the immune system is a key contributor to adult neurogenesis.
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| 13. |
- Boije, Henrik, et al.
(author)
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The Independent Probabilistic Firing of Transcription Factors : A Paradigm for Clonal Variability in the Zebrafish Retina
- 2015
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In: Developmental Cell. - : Elsevier BV. - 1534-5807 .- 1878-1551. ; 34:5, s. 532-543
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Journal article (peer-reviewed)abstract
- Early retinal progenitor cells (RPCs) in vertebrates produce lineages that vary greatly both in terms of cell number and fate composition, yet how this variability is achieved remains unknown. One possibility is that these RPCs are individually distinct and that each gives rise to a unique lineage. Another is that stochastic mechanisms play upon the determinative machinery of equipotent early RPCs to drive clonal variability. Here we show that a simple model, based on the independent firing of key fate-influencing transcription factors, can quantitatively account for the intrinsic clonal variance in the zebrafish retina and predict the distributions of neuronal cell types in clones where one or more of these fates are made unavailable.
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| 14. |
- Böiers, Charlotta, et al.
(author)
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A Human IPS Model Implicates Embryonic B-Myeloid Fate Restriction as Developmental Susceptibility to B Acute Lymphoblastic Leukemia-Associated ETV6-RUNX1
- 2018
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In: Developmental Cell. - : Elsevier BV. - 1534-5807 .- 1878-1551. ; 44:3, s. 7-377
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Journal article (peer-reviewed)abstract
- ETV6-RUNX1 is associated with childhood acute B-lymphoblastic leukemia (cALL) functioning as a first-hit mutation that initiates a clinically silent pre-leukemia in utero. Because lineage commitment hierarchies differ between embryo and adult, and the impact of oncogenes is cell-context dependent, we hypothesized that the childhood affiliation of ETV6-RUNX1 cALL reflects its origins in a progenitor unique to embryonic life. We characterize the first emerging B cells in first-trimester human embryos, identifying a developmentally restricted CD19−IL-7R+ progenitor compartment, which transitions from a myeloid to lymphoid program during ontogeny. This developmental series is recapitulated in differentiating human pluripotent stem cells (hPSCs), thereby providing a model for the initiation of cALL. Genome-engineered hPSCs expressing ETV6-RUNX1 from the endogenous ETV6 locus show expansion of the CD19−IL-7R+ compartment, show a partial block in B lineage commitment, and produce proB cells with aberrant myeloid gene expression signatures and potential: features (collectively) consistent with a pre-leukemic state. Böiers, Richardson et al. explore the potential for a developmental susceptibility to childhood acute lymphoblastic leukemia. Characterization of earliest B cell progenitors in human fetal liver identified a unique progenitor compartment that can be recapitulated using human pluripotent stem cells to model the impact of the pre-leukemia-initiating oncogene ETV6-RUNX1.
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| 15. |
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| 16. |
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| 17. |
- Delerue, Thomas, et al.
(author)
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Bacterial developmental checkpoint that directly monitors cell surface morphogenesis
- 2022
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In: Developmental Cell. - : Elsevier. - 1534-5807 .- 1878-1551. ; 57:3, s. 344-360
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Journal article (peer-reviewed)abstract
- Bacillus subtilis spores are encased in two concentric shells: an outer proteinaceous “coat” and an inner peptidoglycan “cortex,” separated by a membrane. Cortex assembly depends on coat assembly initiation, but how cells achieve this coordination across the membrane is unclear. Here, we report that the protein SpoVID monitors the polymerization state of the coat basement layer via an extension to a functional intracellular LysM domain that arrests sporulation when coat assembly is initiated improperly. Whereas extracellular LysM domains bind mature peptidoglycan, SpoVID LysM binds to the membrane-bound lipid II peptidoglycan precursor. We propose that improper coat assembly exposes the SpoVID LysM domain, which then sequesters lipid II and prevents cortex assembly. SpoVID defines a widespread group of firmicute proteins with a characteristic N-terminal domain and C-terminal peptidoglycan-binding domains that might combine coat and cortex assembly roles to mediate a developmental checkpoint linking the morphogenesis of two spatially separated supramolecular structures.
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| 18. |
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| 19. |
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| 20. |
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| 21. |
- Gaengel, K., et al.
(author)
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The Sphingosine-1-Phosphate Receptor S1PR1 Restricts Sprouting Angiogenesis by Regulating the Interplay between VE-Cadherin and VEGFR2
- 2012
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In: Developmental Cell. - : Elsevier BV. - 1534-5807 .- 1878-1551. ; 23:3, s. 587-599
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Journal article (peer-reviewed)abstract
- Angiogenesis, the process by which new blood vessels arise from preexisting ones, is critical for embryonic development and is an integral part of many disease processes. Recent studies have provided detailed information on how angiogenic sprouts initiate, elongate, and branch, but less is known about how these processes cease. Here, we show that S1PR1, a receptor for the blood-borne bioactive lipid sphingosine-1-phosphate (S1P), is critical for inhibition of angiogenesis and acquisition of vascular stability. Loss of S1PR1 leads to increased endothelial cell sprouting and the formation of ectopic vessel branches. Conversely, S1PR1 signaling inhibits angiogenic sprouting and enhances cell-to-cell adhesion. This correlates with inhibition of vascular endothelial growth factor-A (VEGF-A)-induced signaling and stabilization of vascular endothelial (VE)-cadherin localization at endothelial junctions. Our data suggest that S1PR1 signaling acts as a vascular-intrinsic stabilization mechanism, protecting developing blood vessels against aberrant angiogenic responses.
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| 22. |
- Grommisch, David, et al.
(author)
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Defining the contribution of Troy-positive progenitor cells to the mouse esophageal epithelium
- 2024
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In: Developmental Cell. - 1534-5807 .- 1878-1551. ; 59:10, s. 6-1283
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Journal article (peer-reviewed)abstract
- Progenitor cells adapt their behavior in response to tissue demands. However, the molecular mechanisms controlling esophageal progenitor decisions remain largely unknown. Here, we demonstrate the presence of a Troy (Tnfrsf19)-expressing progenitor subpopulation localized to defined regions along the mouse esophageal axis. Lineage tracing and mathematical modeling demonstrate that Troy-positive progenitor cells are prone to undergoing symmetrical fate choices and contribute to esophageal tissue homeostasis long term. Functionally, TROY inhibits progenitor proliferation and enables commitment to differentiation without affecting fate symmetry. Whereas Troy expression is stable during esophageal homeostasis, progenitor cells downregulate Troy in response to tissue stress, enabling proliferative expansion of basal cells refractory to differentiation and reestablishment of tissue homeostasis. Our results demonstrate functional, spatially restricted progenitor heterogeneity in the esophageal epithelium and identify how dynamic regulation of Troy coordinates tissue generation.
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| 23. |
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| 24. |
- Heldin, Carl-Henrik, et al.
(author)
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A new twist in Smad signaling
- 2006
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In: Developmental Cell. - : Elsevier BV. - 1534-5807 .- 1878-1551. ; 10:6, s. 685-686
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Journal article (other academic/artistic)abstract
- Signaling by members of the TGFbeta family is much dependent on the common-mediator Smad4, which forms transcriptionally active complexes with all receptor-activated Smads (R-Smads). New findings demonstrate that transcriptional intermediary factor 1gamma (TIF1gamma) also can bind to R-Smads, as an alternative to Smad4, and mediate different transcriptional effects.
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| 25. |
- Hennigs, Lars
(author)
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Organizer-Derived WOX5 Signal Maintains Root Columella Stem Cells through Chromatin-Mediated Repression of CDF4 Expression
- 2015
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In: Developmental Cell. - : Elsevier BV. - 1534-5807 .- 1878-1551. ; 33, s. 576-588
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Journal article (peer-reviewed)abstract
- Stem cells in plants and animals are maintained pluripotent by signals from adjacent niche cells. In plants, WUSCHEL HOMEOBOX (WOX) transcription factors are central regulators of stem cell maintenance in different meristem types, yet their molecular mode of action has remained elusive. Here we show that in the Arabidopsis root meristem, the WOX5 protein moves from the root niche organizer, the quiescent center, into the columella stem cells, where it directly represses the transcription factor gene CDF4. This creates a gradient of CDF4 transcription, which promotes differentiation opposite to the WOX5 gradient, allowing stem cell daughter cells to exit the stem cell state. We further show that WOX5 represses CDF4 transcription by recruiting TPL/TPR co-repressors and the histone deacetylase HDA19, which consequently induces histone deacetylation at the CDF4 regulatory region. Our results show that chromatin-mediated repression of differentiation programs is a common strategy in plant and animal stem cell niches.
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