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| Open AccessA short G1 phase imposes constitutive replication stress and fork remodelling in mouse embryonic stem cells
In fast proliferating embryonic stem cells (ESC) the DNA damage response is activated by mechanisms that are as yet elusive. Here, Ahuja et al.link the DNA damage response to replication stress in mouse ESCs, caused by a short G1 phase, and propose fork remodelling as maintaining genome stability in embryos.
- Akshay K. Ahuja
- , Karolina Jodkowska
- & Massimo Lopes
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Article
| Open AccessPeriodic patterning of the Drosophila eye is stabilized by the diffusible activator Scabrous
Patterning in the Drosophila eye is achieved by a series of signalling cascades over several cell distances. Here Gavish et al.model lateral inhibition in the developing eye to understand how developmental noise refines such patterning, identifying a novel activator required for buffering spatial variability.
- Avishai Gavish
- , Arkadi Shwartz
- & Naama Barkai
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Article
| Open AccessMaternal plasma folate impacts differential DNA methylation in an epigenome-wide meta-analysis of newborns
Folic acid is routinely recommended for women trying to conceive to ensure proper fetal development. Here, the authors perform a large epigenomics study to examine which fetal epigenetic changes are associated with varied maternal plasma folate levels.
- Bonnie R. Joubert
- , Herman T. den Dekker
- & Stephanie J. London
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Article
| Open AccessGABAergic interneurons form transient layer-specific circuits in early postnatal neocortex
GABAergic interneurons are key components of cortical circuits, yet their early connectivity is unknown. Here the authors show that during early postnatal development,Nkx2-1-derived interneurons engage in layer-specific and dynamic circuits, which are distinct from those in the mature neocortex.
- Paul G. Anastasiades
- , Andre Marques-Smith
- & Simon J. B. Butt
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Article
| Open AccessAutophagy regulates Notch degradation and modulates stem cell development and neurogenesis
The molecular mechanisms behind how autophagy may impact on developmental pathways and cell fate decisions are unclear. Here Wu et al.identify Notch receptors being taken up into ATG16L1-positive autophagosomes and, using a mouse mutant model, show that changes in autophagy can impact on stem cell fate.
- Xiaoting Wu
- , Angeleen Fleming
- & David C. Rubinsztein
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Article
| Open AccessA role for Mfb1p in region-specific anchorage of high-functioning mitochondria and lifespan in Saccharomyces cerevisiae
Mitochondria are asymmetrically inherited during cell division, a process that can affect cell fate and lifespan. Here the authors describe a mechanism for mitochondrial quality control in yeast that maintains a reservoir of high-functioning mitochondria in mother cells and preserves maternal reproductive capacity.
- Wolfgang M. Pernice
- , Jason D. Vevea
- & Liza A. Pon
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Article
| Open AccessIntegrin signalling regulates the expansion of neuroepithelial progenitors and neurogenesis via Wnt7a and Decorin
The extracellular matrix is suggested to play a role in neurogenesis, but it is unclear what role integrin signalling may play in the developing neuroepithelium. Here, in chick, Long et al. show that expression of constitutively active integrin beta-1 enhances neurogenesis via a novel Wnt7 and decorin pathway.
- K. Long
- , L. Moss
- & C. ffrench-Constant
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Article
| Open AccessEpidermal β-catenin activation remodels the dermis via paracrine signalling to distinct fibroblast lineages
The molecular mechanisms regulating skin dermal changes are unclear. Here, the authors show that deletion of Hedgehog (Hh) in the upper dermis alters the response to epidermal Wnt signalling, which, together with changes in extracellular matrix production, influences distinct fibroblast lineages differently.
- Beate M. Lichtenberger
- , Maria Mastrogiannaki
- & Fiona M. Watt
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Article
| Open AccessDiapause is associated with a change in the polarity of secretion of insulin-like peptides
Insulin-like peptides INS-7 and INS-35 suppress larval diapause in Caenorhabditis elegans via unknown mechanism. Here, Matsunaga et al.show that the secretory polarity of both peptides changes in diapause, when these peptides are secreted into the intestinal lumen instead of the body cavity like in other larval stages.
- Yohei Matsunaga
- , Yoko Honda
- & Tsuyoshi Kawano
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Article
| Open AccessStem cells of the suture mesenchyme in craniofacial bone development, repair and regeneration
The suture mesenchyme has been postulated to act as the niche for stem cells for calvarial bones but the identity of the stem cells is unknown. Here, Maruyama et al.suggest that Axin2 expressing cells act as stem cells not only in craniofacial bone development and homeostasis but in injury-induced repair.
- Takamitsu Maruyama
- , Jaeim Jeong
- & Wei Hsu
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Article
| Open AccessNon-CG DNA methylation is a biomarker for assessing endodermal differentiation capacity in pluripotent stem cells
The methylation of non-CpG residues is a poorly understood marker of pluripotent cells, gradually lost as cells differentiate. Here the authors show non-CG methylation can be used as a marker of differentiation potential.
- Lee M. Butcher
- , Mitsuteru Ito
- & Stephan Beck
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Article
| Open AccessThe Hippo signalling pathway maintains quiescence in Drosophila neural stem cells
Drosophila neural stem cells (NSCs) are quiescent at early larval stages but how this is regulated is unclear. Here, Ding et al. show that quiescence of NSCs is mediated by cell-contact inhibition via the Hippo pathway transmembrane proteins Crumbs and Echinoid, which in turn are regulated by nutrient levels.
- Rouven Ding
- , Kevin Weynans
- & Christian Berger
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Article
| Open AccessE2F function in muscle growth is necessary and sufficient for viability in Drosophila
The transcriptional regulators E2F/Dp play a critical role in cell-cycle regulation, but it is unclear why E2F-deficient flies die. Here, the authors show this is linked to the function of E2F in adult Drosophilaskeletal muscle, with the contribution of E2f1 being most important in post-fusion muscle.
- Maria Paula Zappia
- & Maxim V. Frolov
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Article
| Open AccessThe occurrence of intracranial rhabdoid tumours in mice depends on temporal control of Smarcb1 inactivation
SMARCB1 inactivation is prevalent in human atypical teratoid/rhabdoid tumours but a mouse model that accurately phenocopies the human disease is lacking. Here, the authors show that inactivation of SMARCB1between E6 and E10 in mice results in tumours that better recapitulate the human phenotype, compared to previously reported models.
- Zhi-Yan Han
- , Wilfrid Richer
- & Franck Bourdeaut
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Article
| Open AccessLSD1 co-repressor Rcor2 orchestrates neurogenesis in the developing mouse brain
Epigenetic regulation plays a key role in cortical development. Here the authors show that Rcor2, a co-repressor of the histone demethylase LSD1/KDM1A complex, regulates neural progenitor cell proliferation and cortical neurogenesis by repressing sonic hedgehog signaling.
- Yixuan Wang
- , Qian Wu
- & Xiaoqun Wang
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Article
| Open AccessThe novel tumour suppressor Madm regulates stem cell competition in the Drosophila testis
Stem cell competition mediates the balance between tissue homeostasis and tumour formation, but how this occurs is unclear. Here, Singh et al.show that the tumour suppressor Mlfl-adaptor molecule regulates the balance between germline stem cell and somatic cyst stem cell growth in the Drosophila testis niche.
- Shree Ram Singh
- , Ying Liu
- & Steven X. Hou
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Article
| Open AccessPrevention of Treacher Collins syndrome craniofacial anomalies in mouse models via maternal antioxidant supplementation
The TCOF1 gene is mutated in Treacher Collin's syndrome, a congenital craniofacial syndrome. Here, the authors show that Tcof1loss-of-function results in oxidative stress induced DNA damage and neuroepithelial cell death, and addition of antioxidants to pregnant mutant mice protected against these defects.
- Daisuke Sakai
- , Jill Dixon
- & Paul A. Trainor
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Article
| Open AccessCLIC4 regulates apical exocytosis and renal tube luminogenesis through retromer- and actin-mediated endocytic trafficking
Chloride intracellular channel (CLIC) 4 is an ion channel, localized in the cytoplasm, and first identified as an actin binding protein. Here, Chou et al.knockout CLIC4 in mice and observe tubulogenesis and renal proximal tubule dilation defects, which is caused by irregular actin and endosomal trafficking.
- Szu-Yi Chou
- , Kuo-Shun Hsu
- & Ching-Hwa Sung
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Article
| Open AccessFunctional anterior pituitary generated in self-organizing culture of human embryonic stem cells
It is difficult to generate functional human anterior pituitary tissues in vitro. Here, Ozone et al. generate human anterior pituitary from embryonic stem cells by recapitulating in vivodevelopment, and demonstrate this tissue secretes hormones and rescues hypopituitarism when grafted into mice.
- Chikafumi Ozone
- , Hidetaka Suga
- & Yoshiki Sasai
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Article
| Open AccessReprogramming triggers endogenous L1 and Alu retrotransposition in human induced pluripotent stem cells
Genetic and epigenetic abnormalities have been found to result from reprogramming of differentiated cells into human induced pluripotent stem cells (hiPSCs). Here, Klawitter et al.identify endogenous L1, Alu and SVA mobilization during reprogramming, highlighting the risk of insertional mutagens in hiPSCs.
- Sabine Klawitter
- , Nina V. Fuchs
- & Gerald G. Schumann
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Article
| Open AccessHaematopoietic ESL-1 enables stem cell proliferation in the bone marrow by limiting TGFβ availability
Hematopoietic stem and progenitor cell (HSPCs) proliferation is controlled by signals from the niche. Here, Leivaet al. show in vivoin mice that deletion of E-selectin ligand 1 causes quiescence of HSPCs and a reduction in niche size, which is mediated by changes of TGFß levels in the bone marrow.
- Magdalena Leiva
- , Juan A. Quintana
- & Andrés Hidalgo
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Article
| Open AccessGenetically engineering self-organization of human pluripotent stem cells into a liver bud-like tissue using Gata6
There has been limited success in generating tissues from human induced pluripotent stem cells (hiPSCs). Here, the authors genetically engineer expression of the transcription factor Gata6 in a single isogenic hiPSC population resulting in complex tissue structures that exhibit liver bud-like properties.
- Patrick Guye
- , Mohammad R. Ebrahimkhani
- & Ron Weiss
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Article
| Open AccessReconciling diverse mammalian pigmentation patterns with a fundamental mathematical model
How embryonic melanoblast behaviour influences adult pigmentation patterns and causes patterning defects is unclear. Here, Mort et al. construct a stochastic model parameterised experimentally to show that melanoblast migration is undirected and that reduced proliferation causes patterning defects.
- Richard L. Mort
- , Robert J. H. Ross
- & Christian A. Yates
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Article
| Open AccessHuman pancreatic beta-like cells converted from fibroblasts
Insulin-producing pancreatic beta cells, generatedin vitro, could lead to new anti-diabetic therapies. Here, Zhu et al. convert human fibroblasts into endodermal progenitors that differentiate in vitrointo glucose-responsive beta-like cells that, following transplantation in mice, protect from diabetes.
- Saiyong Zhu
- , Holger A. Russ
- & Sheng Ding
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Article
| Open AccessEmbryonic transcription is controlled by maternally defined chromatin state
Histone modifying enzymes are required for cell differentiation and lineage commitment during embryonic development. By a comprehensive set of epigenome reference maps of Xenopusembryos, the authors show that H3K4me3 and H3K27me3 exert an extended maternal control well into post-gastrulation development.
- Saartje Hontelez
- , Ila van Kruijsbergen
- & Gert Jan C. Veenstra
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Article
| Open AccessEpigenetic regulation of puberty via Zinc finger protein-mediated transcriptional repression
Zinc finger (ZNF) genes are implicated in timing human puberty. Here, the authors show that GATAD1, a ZNF protein, represses transcription of key puberty-activating genes by recruiting histone demethylase KDM1A to their promoters, suggesting GATAD1 epitomizes a subset of ZNFs involved in repression of primate puberty.
- Alejandro Lomniczi
- , Hollis Wright
- & Sergio R. Ojeda
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Article
| Open AccessMBNL1-mediated regulation of differentiation RNAs promotes myofibroblast transformation and the fibrotic response
Fibroblast-to-myofibroblast differentiation is crucial for wound healing and regeneration. Davis et al. describe a new regulatory mechanism underlying myofibroblast differentiation via the RNA-binding protein MBNL1, which promotes the maturation of certain mRNA transcripts that are integral nodes in fibroblast differentiation.
- Jennifer Davis
- , Nathan Salomonis
- & Jeffery D. Molkentin
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Article |
Active JNK-dependent secretion of Drosophila Tyrosyl-tRNA synthetase by loser cells recruits haemocytes during cell competition
Slow-dividing ‘loser’ cells are outcompeted by more robust ‘winner’ cells and eliminated by macrophage-like haemocytes in the fruit fly larva. Here the authors show that the dying loser cells secrete the enzyme Tyrosyl-tRNA synthetase that upon Mmp2-mediated cleavage acts as a haemocyte chemoattractant.
- Sergio Casas-Tintó
- , Fidel-Nicolás Lolo
- & Eduardo Moreno
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Article |
Linc-YY1 promotes myogenic differentiation and muscle regeneration through an interaction with the transcription factor YY1
Long intervening noncoding RNAs (lincRNAs) are an emerging class of molecular regulators with diverse functions. Here the authors identify Linc-YY1, a novel lincRNA transcribed from the noncoding region of the mouse YY1 gene, that binds to YY1 protein and thereby regulates skeletal muscle differentiation and regeneration.
- Liang Zhou
- , Kun Sun
- & Huating Wang
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Article
| Open AccessLeft–right asymmetric cell intercalation drives directional collective cell movement in epithelial morphogenesis
Coordinated epithelial movement during embryogenesis drives complex tissue formation, but how this movement is coordinated to maintain epithelial integrity is not clear. Here the authors show that left-right asymmetry in cell intercalation drives clockwise rotation of epithelia inDrosophilagenital development.
- Katsuhiko Sato
- , Tetsuya Hiraiwa
- & Erina Kuranaga
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Article
| Open AccessCold-sensing regulates Drosophila growth through insulin-producing cells
Animal body size is influenced by climate, but the cellular mechanisms regulating this response are unclear. Here, the authors identify a neuronal circuit composed of a group of cold-sensing neurons and insulin-producing cells that mediates the effects of temperature onDrosophilagrowth.
- Qiaoran Li
- & Zhefeng Gong
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Article
| Open AccessThe Notch and Wnt pathways regulate stemness and differentiation in human fallopian tube organoids
The mechanisms underlying fallopian tube epithelial renewal are unclear. Here, Kessler et al. isolate adult stem cells from the human fallopian tube epithelium and generate 3D organoids from these cells in vitrothat have a similar architecture to that of the fallopian tube.
- Mirjana Kessler
- , Karen Hoffmann
- & Thomas F. Meyer
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Article
| Open AccessTemporal and spatial dynamics of scaling-specific features of a gene regulatory network in Drosophila
How pattern formation is regulated relative to the size of an organism is unclear. Here, Wu et al.take data from gap gene expression in flies of different sizes together with simulations, identifying how scaling emerges dynamically and that local patterning influences global gene regulatory networks.
- Honggang Wu
- , Manu
- & Jun Ma
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Article
| Open AccessCell cycle and p53 gate the direct conversion of human fibroblasts to dopaminergic neurons
The efficiency of reprogramming of fibroblasts into induced dopaminergic neurons is often low. Here, Jiang et al.demonstrate increased transdifferentiation rates by inducing cell cycle arrest, suppressing p53, Tet 1 and by adding neurotrophic factors to the media.
- Houbo Jiang
- , Zhimin Xu
- & Jian Feng
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Article
| Open AccessConcurrent BMP7 and FGF9 signalling governs AP-1 function to promote self-renewal of nephron progenitor cells
The growth factors BMP and FGF both stimulate the self-renewal of nephron progenitor cells (NPCs), but how these signals overlap is unclear. Here in the mouse, Muthukrishnan et al. find BMP7 and FGF9 coordinately regulate AP-1 transcriptional activity, promoting G1-S cell cycle progression and NPC proliferation.
- Sree Deepthi Muthukrishnan
- , Xuehui Yang
- & Leif Oxburgh
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Article
| Open AccessCX3CR1 deficiency promotes muscle repair and regeneration by enhancing macrophage ApoE production
Chemokine-driven infiltration of inflammatory macrophages is central to the muscle regenerative response to injury. Here the authors show that the function of infiltrating macrophages is also important as notexin-induced muscle injury in mice is rescued by CX3CR1 knockout owing to enhanced ApoE production.
- Ludovic Arnold
- , Hélène Perrin
- & Christophe Combadiere
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Article
| Open AccessLSD1 is essential for oocyte meiotic progression by regulating CDC25B expression in mice
At puberty, hormones stimulate mammalian oocytes to resume meiosis, which is linked to dynamic epigenetic changes, but what controls such changes are unknown. Here, Kim et al. identify LSD1, a lysine demethylase, as regulating histone methylation at meiotic progression and also female fertility.
- Jeesun Kim
- , Anup Kumar Singh
- & Taiping Chen
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Article
| Open AccessA redox signalling globin is essential for reproduction in Caenorhabditis elegans
Globins are best known for their role in respiration, but recent studies suggest they might contribute to redox signalling as well. Here, the authors present biochemical, structural and in vivoevidence that the roundworm globin Glb-12 acts as a superoxide generator necessary for germline development.
- Sasha De Henau
- , Lesley Tilleman
- & Bart P. Braeckman
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Article
| Open AccessSTAT5-regulated microRNA-193b controls haematopoietic stem and progenitor cell expansion by modulating cytokine receptor signalling
MicroRNAs regulate haematopoietic stem cell (HSC) development to ensure the correct generation of blood cells. Haetscher et al. show in mice that miR-193b controls the life-long self-renewal ability of HSCs via AKT and STAT5 pathways, with loss of miR-193b accelerating HSC expansion and reducing differentiation.
- Nadine Haetscher
- , Yonatan Feuermann
- & Michael A. Rieger
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Article
| Open AccessControl of developmentally primed erythroid genes by combinatorial co-repressor actions
Conserved sets of transcription factors (TFs) regulate hematopoiesis. Here, Stadhouders et al. show that IRF2BP2 is a component of the LDB1 TF complex and together with its co-repressor ETO2, enhances transcriptional repression, which plays a crucial role at the erythroid progenitor stage.
- Ralph Stadhouders
- , Alba Cico
- & Eric Soler
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Article
| Open AccessHistone H1-mediated epigenetic regulation controls germline stem cell self-renewal by modulating H4K16 acetylation
Epigenetics plays critical roles in controlling stem cell self-renewal and differentiation. Here, Sun et al. show that H1 is intrinsically required in the regulation of germline stem cells in the Drosophilaovary by antagonizing MOF, a histone acetyltransferase specific for H4K16.
- Jin Sun
- , Hui-Min Wei
- & Jian-Quan Ni
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Article
| Open AccessAneuploidy causes premature differentiation of neural and intestinal stem cells
It is unclear why certain tissues are more susceptible to the consequences of aneuploidy. Here, in Drosophila, Gogendeau et al.identify aneuploidy as the cause of lengthened G1 and premature differentiation in both neural and adult intestinal stem cells, which prevents cells with abnormal genomes from cycling.
- Delphine Gogendeau
- , Katarzyna Siudeja
- & Renata Basto
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Article
| Open AccessGeneration of functional hippocampal neurons from self-organizing human embryonic stem cell-derived dorsomedial telencephalic tissue
In vitro differentiation of human pluripotent stem cells (hPSCs) has enabled the generation of neuroectodermal tissues. Here, Sakaguchi et al.use a modified neocortical induction method to generate functional hippocampal granule and pyramidal-like neurons, as well as dorsomedial telencephalic tissues from hPSCs.
- Hideya Sakaguchi
- , Taisuke Kadoshima
- & Yoshiki Sasai
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Article
| Open AccessOocyte-triggered dimerization of sperm IZUMO1 promotes sperm–egg fusion in mice
Sperm-egg fusion is facilitated by the sperm-specific receptor IZUMO1 and the egg-specific counter-receptor JUNO. Here Inoue et al.show that JUNO first binds to monomeric IZUMO1; IZUMO1 then dimerizes and excludes JUNO from the sperm-egg interface, suggesting the existence of a IZUMO1 dimer receptor.
- Naokazu Inoue
- , Yoshihisa Hagihara
- & Ikuo Wada
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Article
| Open AccessComprehensive functional characterization of cancer–testis antigens defines obligate participation in multiple hallmarks of cancer
Proteins usually expressed solely in the testes are often found over-expressed in cancer and are termed cancer testis antigens. Here, the authors use a comprehensive screening strategy to identify 26 cancer-testis antigens that promote tumorigenic behaviour.
- Kimberly E. Maxfield
- , Patrick J. Taus
- & Angelique W. Whitehurst
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Article
| Open AccessESRP2 controls an adult splicing programme in hepatocytes to support postnatal liver maturation
Alternative RNA splicing is important during organismal development. Here, the authors perform RNA-Seq on mouse and human liver samples to provide a comprehensive view of splicing events during liver development and growth, and identify Espr2 as a main regulator of these splicing processes.
- Amruta Bhate
- , Darren J. Parker
- & Auinash Kalsotra
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Article
| Open AccessStem and progenitor cell division kinetics during postnatal mouse mammary gland development
The stem and progenitor populations that regulate mammary gland development are debated. Giraddi et al.use experimental and mathematical approaches to show that the three lineages of the mammary gland are maintained by their own restricted progenitors, and that cycling status links to the oestrus cycle.
- Rajshekhar R. Giraddi
- , Mona Shehata
- & John Stingl
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Article
| Open AccessDilp8 requires the neuronal relaxin receptor Lgr3 to couple growth to developmental timing
The orphan ligand Dilp8 has been shown to coordinate growth and developmental timing in Drosophila. Here, using Gal4 drivers and CRISPR/Cas9 approaches, Garelli et al.identify a role for relaxin-like receptor Lgr3 in regulating the Dilp8 developmental delay pathway.
- Andres Garelli
- , Fabiana Heredia
- & Alisson M. Gontijo
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Article
| Open AccessTorso-like mediates extracellular accumulation of Furin-cleaved Trunk to pattern the Drosophila embryo termini
Activation of the growth factor Trunk patterns the Drosophila embryonic termini but how this is regulated is unclear. Here, Johnson et al.report that Trunk is cleaved intracellularly by Furin proteases, and its extracellular accumulation is then mediated by the perforin-like protein Torso-like.
- Travis K. Johnson
- , Michelle A. Henstridge
- & Coral G. Warr
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