A Novel Role for Ascl1 in the Regulation of Mesendoderm Formation Via
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Prospective Isolation of NKX2-1–Expressing Human Lung Progenitors Derived from Pluripotent Stem Cells
The Journal of Clinical Investigation RESEARCH ARTICLE Prospective isolation of NKX2-1–expressing human lung progenitors derived from pluripotent stem cells Finn Hawkins,1,2 Philipp Kramer,3 Anjali Jacob,1,2 Ian Driver,4 Dylan C. Thomas,1 Katherine B. McCauley,1,2 Nicholas Skvir,1 Ana M. Crane,3 Anita A. Kurmann,1,5 Anthony N. Hollenberg,5 Sinead Nguyen,1 Brandon G. Wong,6 Ahmad S. Khalil,6,7 Sarah X.L. Huang,3,8 Susan Guttentag,9 Jason R. Rock,4 John M. Shannon,10 Brian R. Davis,3 and Darrell N. Kotton1,2 2 1Center for Regenerative Medicine, and The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA. 3Center for Stem Cell and Regenerative Medicine, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, Texas, USA. 4Department of Anatomy, UCSF, San Francisco, California, USA. 5Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA. 6Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, Massachusetts, USA. 7Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts, USA. 8Columbia Center for Translational Immunology & Columbia Center for Human Development, Columbia University Medical Center, New York, New York, USA. 9Department of Pediatrics, Monroe Carell Jr. Children’s Hospital, Vanderbilt University, Nashville, Tennessee, USA. 10Division of Pulmonary Biology, Cincinnati Children’s Hospital, Cincinnati, Ohio, USA. It has been postulated that during human fetal development, all cells of the lung epithelium derive from embryonic, endodermal, NK2 homeobox 1–expressing (NKX2-1+) precursor cells. -
Early Events of Neural Development
Early events of neural development Goals: 1) to discuss the origins of cells in the nervous system 2) to discuss how neural stem cells generate diverse cell types in the nervous system The next four lectures will cover: Induction (Jan 22)...emergence of the nervous system Regionalization (Jan 24)...acquisition of positional information of neural cells Discussion of a journal article (Jan 26) Cell division and cell lineage (Jan 29) Neuronal fate specification (Jan 31) Discussion of a journal article (Feb 2) We will deal with glia later in the course! 1 Outline of this lecture Control of daughter cell fates after cell division (RGC vs differentiating cell) -Notch-Delta signaling -proneural basic helix-loop-helix (bHLH) transcription factors Identity of progenitor cells influence the type of neurons that the progenitor cell produces. -regional identity (outcome of regionalization) -temporal identity (RGCs changes as they undergo asymmetric divisions) Neuronal fate can be controlled postmitotically. 2 Published online: March 17, 2014 EMBO reports Neurogenesis during vertebrate development Judith TML Paridaen & Wieland B Huttner Published online: March 17, 2014 EMBO reports Neurogenesis during vertebrate development Judith TML Paridaen & Wieland B Huttner A C Regulation of spindle orientation Symmetric division Planar Oblique Horizontal NPCA 2 NPCs C Regulation of spindle orientation Mammalian neurogenesis Drosophila neuroblast Symmetric division Planar Oblique Horizontal NPC 2 NPCs Mammalian neurogenesis Drosophila neuroblast Apical Centrosome -
Supplemental Materials ZNF281 Enhances Cardiac Reprogramming
Supplemental Materials ZNF281 enhances cardiac reprogramming by modulating cardiac and inflammatory gene expression Huanyu Zhou, Maria Gabriela Morales, Hisayuki Hashimoto, Matthew E. Dickson, Kunhua Song, Wenduo Ye, Min S. Kim, Hanspeter Niederstrasser, Zhaoning Wang, Beibei Chen, Bruce A. Posner, Rhonda Bassel-Duby and Eric N. Olson Supplemental Table 1; related to Figure 1. Supplemental Table 2; related to Figure 1. Supplemental Table 3; related to the “quantitative mRNA measurement” in Materials and Methods section. Supplemental Table 4; related to the “ChIP-seq, gene ontology and pathway analysis” and “RNA-seq” and gene ontology analysis” in Materials and Methods section. Supplemental Figure S1; related to Figure 1. Supplemental Figure S2; related to Figure 2. Supplemental Figure S3; related to Figure 3. Supplemental Figure S4; related to Figure 4. Supplemental Figure S5; related to Figure 6. Supplemental Table S1. Genes included in human retroviral ORF cDNA library. Gene Gene Gene Gene Gene Gene Gene Gene Symbol Symbol Symbol Symbol Symbol Symbol Symbol Symbol AATF BMP8A CEBPE CTNNB1 ESR2 GDF3 HOXA5 IL17D ADIPOQ BRPF1 CEBPG CUX1 ESRRA GDF6 HOXA6 IL17F ADNP BRPF3 CERS1 CX3CL1 ETS1 GIN1 HOXA7 IL18 AEBP1 BUD31 CERS2 CXCL10 ETS2 GLIS3 HOXB1 IL19 AFF4 C17ORF77 CERS4 CXCL11 ETV3 GMEB1 HOXB13 IL1A AHR C1QTNF4 CFL2 CXCL12 ETV7 GPBP1 HOXB5 IL1B AIMP1 C21ORF66 CHIA CXCL13 FAM3B GPER HOXB6 IL1F3 ALS2CR8 CBFA2T2 CIR1 CXCL14 FAM3D GPI HOXB7 IL1F5 ALX1 CBFA2T3 CITED1 CXCL16 FASLG GREM1 HOXB9 IL1F6 ARGFX CBFB CITED2 CXCL3 FBLN1 GREM2 HOXC4 IL1F7 -
Regulation of the Drosophila ID Protein Extra Macrochaetae by Proneural Dimerization Partners Ke Li1†, Nicholas E Baker1,2,3*
RESEARCH ARTICLE Regulation of the Drosophila ID protein Extra macrochaetae by proneural dimerization partners Ke Li1†, Nicholas E Baker1,2,3* 1Department of Genetics, Albert Einstein College of Medicine, Bronx, United States; 2Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, United States; 3Department of Ophthalmology and Visual Sciences, Albert Einstein College of Medicine, Bronx, United States Abstract Proneural bHLH proteins are transcriptional regulators of neural fate specification. Extra macrochaetae (Emc) forms inactive heterodimers with both proneural bHLH proteins and their bHLH partners (represented in Drosophila by Daughterless). It is generally thought that varying levels of Emc define a prepattern that determines where proneural bHLH genes can be effective. We report that instead it is the bHLH proteins that determine the pattern of Emc levels. Daughterless level sets Emc protein levels in most cells, apparently by stabilizing Emc in heterodimers. Emc is destabilized in proneural regions by local competition for heterodimer formation by proneural bHLH proteins including Atonal or AS-C proteins. Reflecting this post- translational control through protein stability, uniform emc transcription is sufficient for almost normal patterns of neurogenesis. Protein stability regulated by exchanges between bHLH protein *For correspondence: dimers could be a feature of bHLH-mediated developmental events. [email protected] DOI: https://doi.org/10.7554/eLife.33967.001 Present address: †Howard Hughes Medical Institute, Department of Physiology, University of California, San Introduction Francisco, San Francisco, United Proneural bHLH genes play a fundamental role in neurogenesis. Genes from Drosophila such as States atonal (ato) and genes of the Achaete-Scute gene complex (AS-C) define the proneural regions that Competing interests: The have the potential for neural fate (Baker and Brown, 2018; Bertrand et al., 2002; Go´mez- authors declare that no Skarmeta et al., 2003). -
Hes6 Inhibits Astrocyte Differentiation and Promotes Neurogenesis Through Different Mechanisms
The Journal of Neuroscience, October 25, 2006 • 26(43):11061–11071 • 11061 Cellular/Molecular Hes6 Inhibits Astrocyte Differentiation and Promotes Neurogenesis through Different Mechanisms Sumit Jhas, Sorana Ciura,* Stephanie Belanger-Jasmin,* Zhifeng Dong, Estelle Llamosas, Francesca M. Theriault, Kerline Joachim, Yeman Tang, Lauren Liu, Jisheng Liu, and Stefano Stifani Center for Neuronal Survival, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada H3A 2B4 The mechanisms regulating the generation of cell diversity in the mammalian cerebral cortex are beginning to be elucidated. In that regard, Hairy/Enhancer of split (Hes) 1 and 5 are basic helix-loop-helix (bHLH) factors that inhibit the differentiation of pluripotent cortical progenitors into neurons. In contrast, a related Hes family member termed Hes6 promotes neurogenesis. It is shown here that knockdown of endogenous Hes6 causes supernumerary cortical progenitors to differentiate into cells that exhibit an astrocytic morphol- ogy and express the astrocyte marker protein GFAP. Conversely, exogenous Hes6 expression in cortical progenitors inhibits astrocyte differentiation. The negative effect of Hes6 on astrocyte differentiation is independent of its ability to promote neuronal differentiation. We also show that neither its proneuronal nor its anti-gliogenic functions appear to depend on Hes6 ability to bind to DNA via the basic arm of its bHLH domain. Both of these activities require Hes6 to be localized to nuclei, but only its anti-gliogenic function depends on two short peptides, LNHLL and WRPW, that are conserved in all Hes6 proteins. These findings suggest that Hes6 is an important regulator of the neurogenic phase of cortical development by promoting the neuronal fate while suppressing astrocyte differentiation. -
Regulation of Proneural Gene Expression and Cell Fate During Neuroblast Segregation in the Drosophila Embryo
Development 114, 939-946 (1992) 939 Printed in Great Britain © The Company of Biologists Limited 1992 Regulation of proneural gene expression and cell fate during neuroblast segregation in the Drosophila embryo JAMES B. SKEATH and SEAN B. CARROLL* Howard Hughes Medical Institute, Laboratory of Molecular Biology, University of Wisconsin - Madison, 1525 Linden Drive, Madison, WI 53706, USA *To whom correspondence should be addressed Summary The Drosophila embryonic central nervous system expressed in a repeating pattern of four ectodermal cell develops from sets of progenitor neuroblasts which clusters per hemisegment. Even though 5-7 cells initially segregate from the neuroectoderm during early embryo- express ac in each cluster, only one, the neuroblast, genesis. Cells within this region can follow either the continues to express ac. The repression of ac in the neural or epidermal developmental pathway, a decision remaining cells of the cluster requires zygotic neurogenic guided by two opposing classes of genes. The proneural gene function. In embryos lacking any one of five genes, genes, including the members of the achaete-scute the restriction of ac expression to single cells does not complex (AS-C), promote neurogenesis, while the occur; instead, all cells of each cluster continue to neurogenic genes prevent neurogenesis and facilitate express ac, enlarge, delaminate and become neuroblasts. epidermal development. To understand the role that It appears that one key function of the neurogenic genes proneural gene expression and regulation play in the is to silence proneural gene expression within the choice between neurogenesis and epidermogenesis, we nonsegregating cells of the initial ectodermal clusters, examined the temporal and spatial expression pattern of thereby permitting epidermal development. -
E Proteins Sharpen Neurogenesis by Modulating Proneural Bhlh
RESEARCH ARTICLE E proteins sharpen neurogenesis by modulating proneural bHLH transcription factors’ activity in an E-box-dependent manner Gwenvael Le Dre´ au1†*, Rene´ Escalona1†‡, Raquel Fueyo2, Antonio Herrera1, Juan D Martı´nez1, Susana Usieto1, Anghara Menendez3, Sebastian Pons3, Marian A Martinez-Balbas2, Elisa Marti1 1Department of Developmental Biology, Instituto de Biologı´a Molecular de Barcelona, Barcelona, Spain; 2Department of Molecular Genomics, Instituto de Biologı´a Molecular de Barcelona, Barcelona, Spain; 3Department of Cell Biology, Instituto de Biologı´a Molecular de Barcelona, Barcelona, Spain Abstract Class II HLH proteins heterodimerize with class I HLH/E proteins to regulate transcription. Here, we show that E proteins sharpen neurogenesis by adjusting the neurogenic strength of the distinct proneural proteins. We find that inhibiting BMP signaling or its target ID2 in *For correspondence: the chick embryo spinal cord, impairs the neuronal production from progenitors expressing [email protected] ATOH1/ASCL1, but less severely that from progenitors expressing NEUROG1/2/PTF1a. We show this context-dependent response to result from the differential modulation of proneural proteins’ †These authors contributed activity by E proteins. E proteins synergize with proneural proteins when acting on CAGSTG motifs, equally to this work thereby facilitating the activity of ASCL1/ATOH1 which preferentially bind to such motifs. Present address: Conversely, E proteins restrict the neurogenic strength of NEUROG1/2 by directly inhibiting their ‡ Departamento de Embriologı´a, preferential binding to CADATG motifs. Since we find this mechanism to be conserved in Facultad de Medicina, corticogenesis, we propose this differential co-operation of E proteins with proneural proteins as a Universidad Nacional Auto´noma novel though general feature of their mechanism of action. -
Transcription Factor ATF5 Is Required for Terminal Differentiation and Survival of Olfactory Sensory Neurons
Transcription factor ATF5 is required for terminal differentiation and survival of olfactory sensory neurons Shu-Zong Wanga,b, Jianhong Oub, Lihua J. Zhub,c, and Michael R. Greena,b,1 aHoward Hughes Medical Institute, bPrograms in Gene Function and Expression and Molecular Medicine, and cProgram in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605 Edited by Solomon H. Snyder, The Johns Hopkins University School of Medicine, Baltimore, MD, and approved September 27, 2012 (received for review June 21, 2012) Activating transcription factor 5 (ATF5) is a member of the ATF/cAMP not been determined. Here we address this issue by deriving and −/− response element-binding family of transcription factors, which characterizing Atf5 mice. compose a large group of basic region leucine zipper proteins whose members mediate diverse transcriptional regulatory functions. Results −/− ATF5 has a well-established prosurvival activity and has been found Derivation of Atf5 Mice. To investigate the physiological role of −/− to be overexpressed in several human cancers, in particular glioblas- ATF5, we derived Atf5 mice. The gene-targeting strategy in- toma. However, the role(s) of ATF5 in development and normal volved replacing almost the entire coding region of Atf5 with a physiology are unknown. Here we address this issue by deriving LacZ-Neo cassette, such that the LacZ gene is under the control and characterizing homozygous Atf5 knockout mice. We find that of the endogenous Atf5 promoter (Fig. S1A). The genomic struc- +/+ +/− −/− Atf5−/− pups die neonatally, which, as explained below, is consis- ture of the Atf5 locus in Atf5 , Atf5 ,andAtf5 mice was fi tent with an olfactory defect resulting in a competitive suckling con rmed by Southern blot (Fig. -
Molecular Regulation in Dopaminergic Neuron Development
International Journal of Molecular Sciences Review Molecular Regulation in Dopaminergic Neuron Development. Cues to Unveil Molecular Pathogenesis and Pharmacological Targets of Neurodegeneration Floriana Volpicelli 1 , Carla Perrone-Capano 1,2 , Gian Carlo Bellenchi 2,3, Luca Colucci-D’Amato 4,* and Umberto di Porzio 2 1 Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy; fl[email protected] (F.V.); [email protected] (C.P.C.) 2 Institute of Genetics and Biophysics “Adriano Buzzati Traverso”, CNR, 80131 Rome, Italy; [email protected] (G.C.B.); [email protected] (U.d.P.) 3 Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy 4 Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy * Correspondence: [email protected]; Tel.: +39-0823-274577 Received: 28 April 2020; Accepted: 1 June 2020; Published: 3 June 2020 Abstract: The relatively few dopaminergic neurons in the mammalian brain are mostly located in the midbrain and regulate many important neural functions, including motor integration, cognition, emotive behaviors and reward. Therefore, alteration of their function or degeneration leads to severe neurological and neuropsychiatric diseases. Unraveling the mechanisms of midbrain dopaminergic (mDA) phenotype induction and maturation and elucidating the role of the gene network involved in the development and maintenance of these neurons is of pivotal importance to rescue or substitute these cells in order to restore dopaminergic functions. Recently, in addition to morphogens and transcription factors, microRNAs have been identified as critical players to confer mDA identity. The elucidation of the gene network involved in mDA neuron development and function will be crucial to identify early changes of mDA neurons that occur in pre-symptomatic pathological conditions, such as Parkinson’s disease. -
Notch Controls Multiple Pancreatic Cell Fate Regulators Through Direct Hes1-Mediated Repression
bioRxiv preprint doi: https://doi.org/10.1101/336305; this version posted June 1, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Notch Controls Multiple Pancreatic Cell Fate Regulators Through Direct Hes1-mediated Repression by Kristian H. de Lichtenberg1, Philip A. Seymour1, Mette C. Jørgensen1, Yung-Hae Kim1, Anne Grapin-Botton1, Mark A. Magnuson2, Nikolina Nakic3,4, Jorge Ferrer3, Palle Serup1* 1 Novo Nordisk Foundation Center for Stem Cell Biology (Danstem), University of Copenhagen, Denmark. 2 Center for Stem Cell Biology, Vanderbilt University, Tennessee, USA. 3 Section on Epigenetics and Disease, Imperial College London, UK. 4 Current Address: GSK, Stevenage, UK. *Corresponding Author: [email protected] 1 bioRxiv preprint doi: https://doi.org/10.1101/336305; this version posted June 1, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract Notch signaling and its effector Hes1 regulate multiple cell fate choices in the developing pancreas, but few direct target genes are known. Here we use transcriptome analyses combined with chromatin immunoprecipitation with next-generation sequencing (ChIP-seq) to identify direct target genes of Hes1. ChIP-seq analysis of endogenous Hes1 in 266-6 cells, a model of multipotent pancreatic progenitor cells, revealed high-confidence peaks associated with 354 genes. Among these were genes important for tip/trunk segregation such as Ptf1a and Nkx6-1, genes involved in endocrine differentiation such as Insm1 and Dll4, and genes encoding non-pancreatic basic-Helic-Loop-Helix (bHLH) factors such as Neurog2 and Ascl1. -
A Feedback Loop Mediated by Degradation of an Inhibitor Is Required to Initiate Neuronal Differentiation
Downloaded from genesdev.cshlp.org on September 27, 2021 - Published by Cold Spring Harbor Laboratory Press A feedback loop mediated by degradation of an inhibitor is required to initiate neuronal differentiation Dorothy F. Sobieszczuk, Alexei Poliakov, Qiling Xu, and David G. Wilkinson1 Division of Developmental Neurobiology, MRC National Institute for Medical Research, London NW7 1AA, United Kingdom Neuronal differentiation is regulated by proneural genes that promote neurogenesis and inhibitory mechanisms that maintain progenitors. This raises the question of how the up-regulation of proneural genes required to initiate neurogenesis occurs in the presence of such inhibition. We carried out loss and gain of gene function, an interaction screen for binding partners, and biochemical analyses to uncover the regulation, developmental role, and mechanism of action of a ubiquitination adaptor protein, Btbd6a (BTB domain containing 6a). We find that the proneural gene neurog1 up-regulates btbd6a, which in turn is required for up-regulation of neurog1. Btbd6a is an adaptor for the Cul3 ubiquitin ligase complex, and we find that it binds to the transcriptional repressor Plzf (promyelocytic leukemia zinc finger). Btbd6a promotes the relocation of Plzf from nucleus to cytoplasm and targets Plzf for ubiquitination and degradation. plzfa is expressed widely in the neural epithelium; when overexpressed, it inhibits neurogenesis, and this inhibition is reversed by btbd6a. The antagonism of endogenous plzfa by btbd6a is required for neurogenesis, since the block in neuronal differentiation caused by btbd6a knockdown is alleviated by plzfa knockdown. These findings reveal a feedback loop mediated by degradation of an inhibitor that is essential for progenitors to undergo the transition to neuronal differentiation. -
The Doublesex-Related Dmrta2 Safeguards Neural Progenitor
The doublesex-related Dmrta2 safeguards neural PNAS PLUS progenitor maintenance involving transcriptional regulation of Hes1 Fraser I. Younga, Marc Keruzoreb,1, Xinsheng Nanc,1, Nicole Genneta, Eric J. Bellefroidb,2, and Meng Lia,c,2 aNeuroscience and Mental Health Research Institute, School of Medicine, Cardiff University, Cardiff CF24 4HQ, United Kingdom; bInstitute of Neuroscience, Université Libre de Bruxelles, B-6041 Gosselies, Belgium; and cSchool of Bioscience, Cardiff University, Cardiff CF24 4HQ, United Kingdom Edited by Anders Bjorklund, Lund University, Lund, Sweden, and approved May 16, 2017 (received for review March 29, 2017) The mechanisms that determine whether a neural progenitor cell onic brain, however (9, 10). Dmrta2 loss of function in zebrafish (NPC) reenters the cell cycle or exits and differentiates are pivotal for leads to significant reductions in cortical size, coupled with re- generating cells in the correct numbers and diverse types, and thus duced neuronal numbers (10, 11). Likewise, a smaller neocortex, dictate proper brain development. Combining gain-of-function and particularly the dorsomedial neocortex, has been observed in mice loss-of-function approaches in an embryonic stem cell-derived cortical carrying null deletions of Dmrta2 (12–14). Together with the as- differentiation model, we report that doublesex- and mab-3–related sociation of DMRTA2 mutation and microlissencephaly in humans, transcription factor a2 (Dmrta2, also known as Dmrt5) plays an im- these findings implicate Dmrta2 as an important regulator for cortical portant role in maintaining NPCs in the cell cycle. Temporally controlled neurogenesis. expression of transgenic Dmrta2 in NPCs suppresses differentiation Dmrta2-null mice also exhibit agenesis of the embryonic cor- Dmrta2 without affecting their neurogenic competence.