DOCSLIB.ORG

Intracellular Communication Among Morphogen Signaling Pathways During Vertebrate Body Plan Formation

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Intracellular Communication Among Morphogen Signaling Pathways During Vertebrate Body Plan Formation G C A T T A C G G C A T genes Review Intracellular Communication among Morphogen Signaling Pathways during Vertebrate Body Plan Formation Kimiko Takebayashi-Suzuki 1,* and Atsushi Suzuki 2,* 1 Amphibian Research Center, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526, Japan 2 Graduate School of Integrated Sciences for Life, Amphibian Research Center, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima, 739-8526, Japan * Correspondence: [email protected] (K.T.-S.); [email protected] (A.S.); Tel.: +81-82-424-7104 (K.T.-S.); +81-82-424-7103 (A.S.) Received: 23 February 2020; Accepted: 19 March 2020; Published: 24 March 2020 Abstract: During embryonic development in vertebrates, morphogens play an important role in cell fate determination and morphogenesis. Bone morphogenetic proteins (BMPs) belonging to the transforming growth factor-β (TGF-β) family control the dorsal–ventral (DV) patterning of embryos, whereas other morphogens such as fibroblast growth factor (FGF), Wnt family members, and retinoic acid (RA) regulate the formation of the anterior–posterior (AP) axis. Activation of morphogen signaling results in changes in the expression of target genes including transcription factors that direct cell fate along the body axes. To ensure the correct establishment of the body plan, the processes of DV and AP axis formation must be linked and coordinately regulated by a fine-tuning of morphogen signaling. In this review, we focus on the interplay of various intracellular regulatory mechanisms and discuss how communication among morphogen signaling pathways modulates body axis formation in vertebrate embryos. Keywords: BMP; FGF; Wnt; retinoic acid; dorsal–ventral and anterior–posterior axis formation 1. Introduction A morphogen is defined as a molecule released from a localized source that determines several different cell fates and controls morphogenesis by regulating gene expression in a concentration-dependent manner [1,2]. During embryonic development, most morphogens are secreted molecules that bind to transmembrane receptors, activate intracellular signal transducers, and then regulate the expression of downstream target genes. Well-known morphogens are bone morphogenetic proteins (BMPs), Nodals, and Activins, which all belong to the transforming growth factor-β (TGF-β) family, fibroblast growth factors (FGFs), and Wnt family proteins [3–15]. There are a few exceptions to the typical morphogen: retinoic acid (RA), a small compound synthesized from vitamin A (all-trans-retinol), works as a morphogen in embryos [16–19], and Bicoid functions as a morphogen transcription factor in the syncytial blastoderm of Drosophila embryo that contains many nuclei in a large cytoplasm [20]. In early Xenopus embryos, the regulation of body axis formation by morphogens has been thoroughly investigated, and it has been shown that a gradient of BMP signaling determines the dorsal–ventral (DV) axis (Figure1). During gastrulation, ventral ectodermal cells with high BMP signaling acquire an epidermal fate; however, ectodermal cells close to the dorsal marginal zone (Spemann’s organizer), where genes for BMP antagonists (noggin, chordin, and follistatin) are expressed, cannot receive BMP signaling and adopt a neural fate [4,14,15,21–25]. BMP ligands bind to two different Genes 2020, 11, 341; doi:10.3390/genes11030341 www.mdpi.com/journal/genes Genes 2020, 11, 341 2 of 16 Genes 2020, 11, x FOR PEER REVIEW 2 of 16 transmembrane serine/threonine kinase receptors (type I and type II) and activate cellular responses to cellularinduce biologicalresponses functions to induce [6 biological,7,26–32]. Afterfunctions BMP [6,7,26–32]. ligand binding, After the BMP type ligand II receptor binding, forms the a complex type II receptorwith a type forms I receptor a complex and with phosphorylates a type I receptor/activates and thephosphorylates/activates type I receptor, leading the to type the subsequentI receptor, leadingC-terminal to the phosphorylation subsequent C-terminal of the signal phosphorylation transducer Smad1 of the/ 5signal/8 in the transducer cytosol. Smad1/5/8 The C-terminally in the cytosol.phosphorylated The C-terminally Smad1/5 /8phosphorylated (pSmad1/5/8) oligomerizesSmad1/5/8 (pSmad1/5/8) with Smad4 oligomerizes and then translocates with Smad4 into and the thennucleus. translocates In the nucleus, into the a nucleus. complex In of the pSmad1 nucleus,/5/8 a and complex Smad4 of interacts pSmad1/5/8 with and other Smad4 accessory interacts molecules with otherand functions accessory as molecules a transcriptional and functions activator as ora transcri repressor.ptional A high activator level ofor BMPrepressor. signaling A high induces level theof BMPexpression signaling of the induces BMP downstreamthe expression target of the genes BMPap-2 downstream (tfap2a), dlx3 target/5, vent-2 genes (ventx2.2) ap-2 (tfap2a), and, dlx3/5msx1 ,on vent- the 2ventral (ventx2.2) side, and of gastrula msx1 on embryos the ventral and side downregulates of gastrula embr the expressionyos and downregulates of neural marker the expression genes such of as neuralsox2 and markerncam [ 33genes–38]. Assuch a result, as sox2 BMPs and determine ncam the[33–38]. epidermal As /aventral result, fate BMPs while suppressingdetermine the the epidermal/ventralneural/dorsal fate fate and while regulate suppressing the DV axis the of neural/dor embryos. sal fate and regulate the DV axis of embryos. Figure 1. Cell fate specification by morphogen signaling during body axis formation in Xenopus Figureembryos. 1. Cell (A) Atfate the specification gastrula stage, by morphogen bone morphogenetic signaling proteinduring (BMP)body axis and formation Wnt ligands in promoteXenopus embryos.the epidermal (A) At fate the ofgastrula the ectoderm stage, bone on the morphogeneti ventral side.c protein Neural (BMP) tissue and is formed Wnt ligands from thepromote ectoderm the epidermalwhen BMPs fate are of inhibited the ectoderm by BMP on antagoniststhe ventral (anti-BMP;side. Neural Noggin, tissue is Chordin, formed andfrom Follistatin) the ectoderm emanating when BMPsfrom theare inhibited dorsal mesoderm by BMP antagonists (Spemann’s (anti-BMP; organizer), Noggin, which Chordin, later becomes and Follistatin) the notochord. emanating (B) By from the theneurula dorsal stage, mesoderm the induced (Spemann’s neural organizer) tissue is regionalized, which later along becomes the anterior-posteriorthe notochord. (B) (AP)By the axis neurula by the stage,posteriorizing the induced factors neural fibroblast tissue growth is regionalized factor (FGF), along Wnt, andthe retinoicanterior-posterior acid (RA), and(AP) the axis neural by platethe posteriorizingabove the notochord factors fibroblast forms the growth neural tubefactor which (FGF), will Wnt, develop and retinoic into the acid brain (RA), and and spinal the neural cord. ( plateC) By abovethe tadpole the notochord stage, a variety forms ofthe organs neural and tube tissues which such will as develop brain, eyes, into somites,the brain and and tail spinal are formedcord. (C along) By thethe tadpole dorsal–ventral stage, a (DV) variety (back–belly) of organs andand APtissues (head–tail) such as axes. brain, Green, eyes, neuralsomites,/dorsal and tail ectoderm; are formed blue, alongepidermal the dorsal–ventral/ventral ectoderm; (DV) orange, (back–belly) mesoderm and AP (marginal (head–tail) zone); axes. yellow, Green, endoderm. neural/dorsal ectoderm; blue, epidermal/ventral ectoderm; orange, mesoderm (marginal zone); yellow, endoderm. The anterior-posterior (AP) patterning of embryos is regulated by FGF, Wnt, and RA signaling (FigureThe1 )[anterior-posterior8,39–42]. FGF (AP) signaling patterning is transduced of embryo bys is tyrosine regulated kinase by FGF, receptors Wnt, and and RA activates signaling the (Figuremitogen-activated 1) [8,39–42]. kinase FGF signaling (MAPK) is pathway transduced consisting by tyrosine of MAPKKKs kinase receptors (Ras and and Raf), activates MAPKKs, the mitogen-activatedand MAPKs (also kinase called (MAPK) MEKs and pathway ERKs, consis respectively)ting of MAPKKKs [12,13]. FGF4 (Ras induces and Raf), the MAPKKs, expression and of MAPKshomeobox (also genes, called such MEKs as andhoxa7, ERKs, hoxb9, respectively) hoxc6, and [12,13].caudal FGF4-related induces genes, the that expression have important of homeobox roles genes,in the such patterning as hoxa7, of the hoxb9, AP axis;hoxc6 some, and ofcaudal these-related genes genes, have alsothat ahave role inimportant suppressing roles anteriorin the patterningdevelopment of the [43 AP–47 ].axis; Wnt some ligands of these form genes a complex have also with a role the in multi-pass suppressing transmembrane anterior development receptor [43–47].Frizzled Wnt and ligands the Wnt form co-receptors a complex of thewith low-density the multi-pass lipoprotein transmembrane (LDL) receptor-related receptor Frizzled protein and (Lrp) the Wntfamily, co-receptors specifically of Lrp5 the and low-density Lrp6, and thislipoprotei interactionn (LDL) results receptor-related in the stabilization protein of β -Catenin(Lrp) family, in the specificallycytoplasm [48Lrp5–52 ].and Accumulated Lrp6, and βthis-Catenin interaction translocates results into in thethe nucleusstabilization and induces of β-Catenin the expression in the cytoplasmof Wnt target [48–52 genes.]. Accumulated In the absence β-Catenin of Wnt ligands, translocates glycogen into synthasethe nucleus kinase-3 and inducesβ (GSK-3 theβ) participatesexpression
Load more

Recommended publications
  • Functional Analysis of the Homeobox Gene Tur-2 During Mouse Embryogenesis
    Functional Analysis of The Homeobox Gene Tur-2 During Mouse Embryogenesis Shao Jun Tang A thesis submitted in conformity with the requirements for the Degree of Doctor of Philosophy Graduate Department of Molecular and Medical Genetics University of Toronto March, 1998 Copyright by Shao Jun Tang (1998) National Library Bibriothèque nationale du Canada Acquisitions and Acquisitions et Bibiiographic Services seMces bibliographiques 395 Wellington Street 395, rue Weifington OtbawaON K1AW OttawaON KYAON4 Canada Canada The author has granted a non- L'auteur a accordé une licence non exclusive licence alIowing the exclusive permettant à la National Library of Canada to Bibliothèque nationale du Canada de reproduce, loan, distri%uteor sell reproduire, prêter' distribuer ou copies of this thesis in microform, vendre des copies de cette thèse sous paper or electronic formats. la forme de microfiche/nlm, de reproduction sur papier ou sur format électronique. The author retains ownership of the L'auteur conserve la propriété du copyright in this thesis. Neither the droit d'auteur qui protège cette thèse. thesis nor substantial extracts fkom it Ni la thèse ni des extraits substantiels may be printed or otherwise de celle-ci ne doivent être imprimés reproduced without the author's ou autrement reproduits sans son permission. autorisation. Functional Analysis of The Homeobox Gene TLr-2 During Mouse Embryogenesis Doctor of Philosophy (1998) Shao Jun Tang Graduate Department of Moiecular and Medicd Genetics University of Toronto Abstract This thesis describes the clonhg of the TLx-2 homeobox gene, the determination of its developmental expression, the characterization of its fiuiction in mouse mesodem and penpheral nervous system (PNS) developrnent, the regulation of nx-2 expression in the early mouse embryo by BMP signalling, and the modulation of the function of nX-2 protein by the 14-3-3 signalling protein during neural development.
    [Show full text]
  • Visualizing Morphogenesis with the Processing Programming Language 15
    Visualizing Morphogenesis with the Processing Programming Language 15 Visualizing Morphogenesis with the Processing Programming Language Avik Patel, Amar Bains, Richard Millet, and Tamira Elul changing tissue shapes. A powerful technique for elucidating the We used Processing, a visual artists’ programming dynamic cellular mechanisms of morphogenesis is time-lapse video- language developed at MIT Media Lab, to simulate microscopic imaging of cells in embryonic tissues undergoing cellular mechanisms of morphogenesis – the generation morphogenesis (Elul and Keller 2000; Elul et al., 1997; Harris et al., of form and shape in embryonic tissues. Based on 1987). The mechanisms underlying morphogenetic processes can be clarified by observation of cell dynamics from these time-lapse video observations of in vivo time-lapse image sequences, we sequences. Morphometric measurement further defines the created animations of neural cell motility responsible for quantitative and statistical relationships between the cell dynamics that elongating the spinal cord, and of optic axon branching underlie morphogenesis (Kim and Davidson 2011; Marshak et al., dynamics that establish primary visual connectivity. 2007; Elul et al., 1997; Witte et al., 1996). Mathematical These visual models underscore the significance of the decomposition of cell dynamics additionally facilitates the computational decomposition of cellular dynamics computational modeling of cellular mechanisms that drive underlying morphogenesis. morphogenesis (Satulovsky et al., 2008). Methods In this paper, we use the Processing programming language to visualize dynamic cell behaviors driving morphogenesis in the Introduction developing nervous system. Based on in vivo time-lapse image sequences, we created models of cell dynamics underlying two Processing is a Java based software language and environment morphogenetic processes in the developing nervous system.
    [Show full text]
  • Transformations of Lamarckism Vienna Series in Theoretical Biology Gerd B
    Transformations of Lamarckism Vienna Series in Theoretical Biology Gerd B. M ü ller, G ü nter P. Wagner, and Werner Callebaut, editors The Evolution of Cognition , edited by Cecilia Heyes and Ludwig Huber, 2000 Origination of Organismal Form: Beyond the Gene in Development and Evolutionary Biology , edited by Gerd B. M ü ller and Stuart A. Newman, 2003 Environment, Development, and Evolution: Toward a Synthesis , edited by Brian K. Hall, Roy D. Pearson, and Gerd B. M ü ller, 2004 Evolution of Communication Systems: A Comparative Approach , edited by D. Kimbrough Oller and Ulrike Griebel, 2004 Modularity: Understanding the Development and Evolution of Natural Complex Systems , edited by Werner Callebaut and Diego Rasskin-Gutman, 2005 Compositional Evolution: The Impact of Sex, Symbiosis, and Modularity on the Gradualist Framework of Evolution , by Richard A. Watson, 2006 Biological Emergences: Evolution by Natural Experiment , by Robert G. B. Reid, 2007 Modeling Biology: Structure, Behaviors, Evolution , edited by Manfred D. Laubichler and Gerd B. M ü ller, 2007 Evolution of Communicative Flexibility: Complexity, Creativity, and Adaptability in Human and Animal Communication , edited by Kimbrough D. Oller and Ulrike Griebel, 2008 Functions in Biological and Artifi cial Worlds: Comparative Philosophical Perspectives , edited by Ulrich Krohs and Peter Kroes, 2009 Cognitive Biology: Evolutionary and Developmental Perspectives on Mind, Brain, and Behavior , edited by Luca Tommasi, Mary A. Peterson, and Lynn Nadel, 2009 Innovation in Cultural Systems: Contributions from Evolutionary Anthropology , edited by Michael J. O ’ Brien and Stephen J. Shennan, 2010 The Major Transitions in Evolution Revisited , edited by Brett Calcott and Kim Sterelny, 2011 Transformations of Lamarckism: From Subtle Fluids to Molecular Biology , edited by Snait B.
    [Show full text]
  • The Mechanisms of Hedgehog Signal Transduction
    Markku Varjosalo The Mechanisms of Hedgehog Signal Transduction Publications of the National Public Health Institute A 12/2008 Department of Molecular Medicine National Public Health Institute and Institute of Biomedicine, University of Helsinki, Finland Helsinki, Finland 2008 Markku Varjosalo THE MECHANISMS OF HEDGEHOG SIGNAL TRANSDUCTION ACADEMIC DISSERTATION To be publicly discussed with the permission of the Faculty of Medicine, University of Helsinki, in Lecture Hall 2, Biomedicum Helsinki, on 2nd May 2008, at noon. National Public Health Institute, Helsinki, Finland and Institute of Biomedicine, University of Helsinki, Finland Helsinki 2008 Publications of the National Public Health Institute KTL A12 / 2008 Copyright National Public Health Institute Julkaisija-Utgivare-Publisher Kansanterveyslaitos (KTL) Mannerheimintie 166 00300 Helsinki Puh. vaihde (09) 474 41, telefax (09) 4744 8408 Folkhälsoinstitutet Mannerheimvägen 166 00300 Helsingfors Tel. växel (09) 474 41, telefax (09) 4744 8408 National Public Health Institute Mannerheimintie 166 FIN-00300 Helsinki, Finland Telephone +358 9 474 41, telefax +358 9 4744 8408 ISBN 978-951-740-805-9 ISSN 0359-3584 ISBN 978-951-740-806-6 (pdf) ISSN 1458-6290 (pdf) Kannen kuva - cover graphic: Yliopistopaino Helsinki 2008 Supervised by Academy Professor Jussi Taipale Genome-Scale Biology Program Institute of Biomedicine, University of Helsinki Department of Molecular Medicine National Public Health Institute (KTL) Helsinki, Finland Reviewed by Professor Tomi Mäkelä Genome-Scale Biology Program
    [Show full text]
  • Products for Morphogen Research
    R&D Systems Tools for Cell Biology Research™ Products for Morphogen Research BMP-4 NEURAL PLATE BMP-7 PROSPECTIVE NEURAL CREST NON-NEURAL ECTODERM Noggin Shh Noggin PRESOMITIC MESODERM NOTOCHORD NON-NEURAL ECTODERM FUTURE FLOOR PLATE BMP-4 Shh Noggin DORSAL AORTA ROOF PLATE Products for Morphogen Research for Products Noggin Wnt-1 Wnt-3a Wnt-4 NT-3 Wnt-6 Wnt-7a EARLY SOMITE Myf5 NEURAL TUBE Pax3 Sim1 BMP-4 INTERMEDIATE MESODERM Shh ShhShh NogginNoggin BMP-4 DORSAL AORTA Ihh NOTOCHORD MORPHOGENS Morphogens are molecules that regulate cell fate during development. Formation of morphogen concentration gradients directs the biological responses of surrounding cells. Graded responses occur as a result of morphogens binding to specific cell surface receptors that subsequently activate intracellular signaling pathways and promote or repress gene expression at specific threshold concentrations. Activation or inactivation of these signaling pathways provides positional information that ultimately determines tissue organization and morphology. Research in model organisms has revealed that morphogens are involved in many aspects of development. For example, morphogens are required in Drosophila for patterning of the dorso-ventral and anterior-posterior axes, segment patterning, and positional signaling in the leg and wing imaginal discs. Proteins belonging to the Wingless/Wnt, Notch, Hedgehog, and TGF-b families have been identified as morphogens that direct a number of these processes. Research in higher organisms has demonstrated that homologues of these same signaling molecules regulate vertebrate axis formation, anterior/posterior polarity during limb development, mesoderm patterning, and numerous other processes that establish an organism’s basic body structure. R&D Systems offers a wide selection of proteins, antibodies, and ELISAs for morphogen-related developmental research.
    [Show full text]
  • Dynamics of Maternal Morphogen Gradients in Drosophila Stanislav Y Shvartsman1, Mathieu Coppey1 and Alexander M Berezhkovskii2
    COGEDE-512; NO OF PAGES 6 Available online at www.sciencedirect.com Dynamics of maternal morphogen gradients in Drosophila Stanislav Y Shvartsman1, Mathieu Coppey1 and Alexander M Berezhkovskii2 The first direct studies of morphogen gradients were done in ified genes [1]. Since most of these studies were done the end of 1980s, in the early Drosophila embryo, which is with fixed embryos, maternal gradients were viewed as patterned under the action of four maternally determined relatively static signals. Several recent studies report morphogens. Since the early studies of maternal morphogens quantitative measurements of the anterior, dorsoventral, were done with fixed embryos, they were viewed as relatively and terminal gradients and propose biophysical models static signals. Several recent studies analyze dynamics of the for their formation and interpretation. We review these anterior, dorsoventral, and terminal patterning signals. The studies and discuss how their conclusions affect our view results of these quantitative studies provide critical tests of of dynamics in one of the most extensively studied classical models and reveal new modes of morphogen patterning systems. regulation and readout in one of the most extensively studied patterning systems. Bicoid gradient: diffusion and reversible Addresses trapping of a stable protein? 1 Department of Chemical Engineering and Lewis-Sigler Institute for In the end of 1980s, studies of the distribution and Integrative Genomics, Princeton University, New Jersey, United States transcriptional effects of the Bicoid (Bcd) protein in 2 Mathematical and Statistical Computing Laboratory, Division of Computational Bioscience, Center for Information Technology, National the Drosophila embryo provided the first molecularly Institutes of Health, Bethesda, MD 20892, United States defined example of a morphogen gradient [2–4].
    [Show full text]
  • Rapid Changes in Morphogen Concentration Control Self-Organized
    RESEARCH COMMUNICATION Rapid changes in morphogen concentration control self-organized patterning in human embryonic stem cells Idse Heemskerk1†, Kari Burt1, Matthew Miller1, Sapna Chhabra2, M Cecilia Guerra1, Lizhong Liu1, Aryeh Warmflash1,3* 1Department of Biosciences, Rice University, Houston, United States; 2Systems, Synthetic and Physical Biology Program, Rice University, Houston, United States; 3Department of Bioengineering, Rice University, Houston, United States Abstract During embryonic development, diffusible signaling molecules called morphogens are thought to determine cell fates in a concentration-dependent way. Yet, in mammalian embryos, concentrations change rapidly compared to the time for making cell fate decisions. Here, we use human embryonic stem cells (hESCs) to address how changing morphogen levels influence differentiation, focusing on how BMP4 and Nodal signaling govern the cell-fate decisions associated with gastrulation. We show that BMP4 response is concentration dependent, but that expression of many Nodal targets depends on rate of concentration change. Moreover, in a self- organized stem cell model for human gastrulation, expression of these genes follows rapid changes in endogenous Nodal signaling. Our study shows a striking contrast between the specific ways ligand dynamics are interpreted by two closely related signaling pathways, highlighting both the *For correspondence: subtlety and importance of morphogen dynamics for understanding mammalian embryogenesis [email protected] and designing optimized protocols for directed stem cell differentiation. Editorial note: This article has been through an editorial process in which the authors decide how † Present address: Department to respond to the issues raised during peer review. The Reviewing Editor’s assessment is that all of Cell and Developmental the issues have been addressed (see decision letter).
    [Show full text]
  • Differentiating Mesoderm and Muscle Cell Lineages During Drosophila Embryogenesis BRENDA LILLY, SAMUEL GALEWSKY, ANTHONY B
    Proc. Nati. Acad. Sci. USA Vol. 91, pp. 5662-5666, June 1994 Developmental Biology D-MEF2: A MADS box transcription factor expressed in differentiating mesoderm and muscle cell lineages during Drosophila embryogenesis BRENDA LILLY, SAMUEL GALEWSKY, ANTHONY B. FIRULLI, ROBERT A. SCHULZ, AND ERIC N. OLSON* Department of Biochemistry and Molecular Biology, Box 117, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030 Communicated by Thomas P. Maniatis, January 21, 1994 ABSTRACT The myocyte enhancer factor (MEF) 2 family cle-specific genes (13). The recent cloning of MEF2 has oftranscription factors has been Implicated In the regultion of revealed that it belongs to the MADS (MCM1, Agamous, musle tansription in vertebrates. We have cloned a protein Deficiens, and serum-response factor) family oftranscription fromDrosophia, termed D-MEF2, that shares extensive amino factors. Four MEF2 genes, designated MEF2A, -B, -C, and acid homology with the MADS (MCM1, Agamous, Defdcens, -D, have been cloned from vertebrates (10, 14-19). The and serum-response factor) d of the vertebrate MEF2 proteins encoded by these genes are highly homologous proteins. D-mef2 gene expression Is first detected dring within the 55-amino-acid MADS domain at their amino Drosophila embryogenesis within mesodermal precursor cells termini and within an adjacent MEF2-specific region of 27 prior to spcation of the somatic and visceral muscle lin- residues, but they diverge outside of these regions. eages. Expression of D-mef2 Is dependent on the mesodermal We have cloned aDrosophila homologue ofMEF2, termed determinants twist and snail but independent ofthe homeobox- D-MEF2,t which, to our knowledge, is the first MADS containng gene dtnman, which is required for visceral muscle protein to be identified in Drosophila.
    [Show full text]
  • Dynamics of the Dorsal Morphogen Gradient
    Dynamics of the Dorsal morphogen gradient Jitendra S. Kanodiaa, Richa Rikhyb, Yoosik Kima, Viktor K. Lundc, Robert DeLottoc, Jennifer Lippincott-Schwartzb,1, and Stanislav Y. Shvartsmana,1 aDepartment of Chemical Engineering and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Washington Road, Princeton, NJ 08544; bCell Biology and Metabolism Branch, NIH, Building 32, 18 Library Drive, Bethesda, MD 20892; and cDepartment of Molecular Biology, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen, Denmark Contributed by Jennifer Lippincott-Schwartz, October 28, 2009 (sent for review September 6, 2009) The dorsoventral (DV) patterning of the Drosophila embryo depends several minutes (16). Nuclei change in volume and undergo five on the nuclear localization gradient of Dorsal (Dl), a protein related to synchronous divisions (15, 17). To explore how these processes the mammalian NF-␬B transcription factors. Current understanding of contribute to the formation of the Dl gradient, we formulated a how the Dl gradient works has been derived from studies of its mathematical model that accounts for the nuclear import and transcriptional interpretation, but the gradient itself has not been export of Dl, its interaction with Cact, and the dynamics of nuclear quantified. In particular, it is not known whether the Dl gradient is density and volumes in the syncytial blastoderm. Based on the stable or dynamic during the DV patterning of the embryo. To address computational analysis of this model and a number of our model- this question, we developed a mathematical model of the Dl gradient based experiments, we argue that the Dl gradient is dynamic and, and constrained its parameters by experimental data.
    [Show full text]
  • Nicotinic Receptor Alpha7 Expression During Tooth Morphogenesis Reveals Functional Pleiotropy
    Nicotinic Receptor Alpha7 Expression during Tooth Morphogenesis Reveals Functional Pleiotropy Scott W. Rogers1,2*, Lorise C. Gahring1,3 1 Geriatric Research, Education and Clinical Center, Veteran’s Administration, Salt Lake City, Utah, United States of America, 2 Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, Utah, United States of America, 3 Division of Geriatrics, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, United States of America Abstract The expression of nicotinic acetylcholine receptor (nAChR) subtype, alpha7, was investigated in the developing teeth of mice that were modified through homologous recombination to express a bi-cistronic IRES-driven tau-enhanced green fluorescent protein (GFP); alpha7GFP) or IRES-Cre (alpha7Cre). The expression of alpha7GFP was detected first in cells of the condensing mesenchyme at embryonic (E) day E13.5 where it intensifies through E14.5. This expression ends abruptly at E15.5, but was again observed in ameloblasts of incisors at E16.5 or molar ameloblasts by E17.5–E18.5. This expression remains detectable until molar enamel deposition is completed or throughout life as in the constantly erupting mouse incisors. The expression of alpha7GFP also identifies all stages of innervation of the tooth organ. Ablation of the alpha7-cell lineage using a conditional alpha7Cre6ROSA26-LoxP(diphtheria toxin A) strategy substantially reduced the mesenchyme and this corresponded with excessive epithelium overgrowth consistent with an instructive role by these cells during ectoderm patterning. However, alpha7knock-out (KO) mice exhibited normal tooth size and shape indicating that under normal conditions alpha7 expression is dispensable to this process.
    [Show full text]
  • Annominer Is a New Web-Tool to Integrate Epigenetics, Transcription
    www.nature.com/scientificreports OPEN AnnoMiner is a new web‑tool to integrate epigenetics, transcription factor occupancy and transcriptomics data to predict transcriptional regulators Arno Meiler1,3, Fabio Marchiano2,3, Margaux Haering2, Manuela Weitkunat1, Frank Schnorrer1,2 & Bianca H. Habermann1,2* Gene expression regulation requires precise transcriptional programs, led by transcription factors in combination with epigenetic events. Recent advances in epigenomic and transcriptomic techniques provided insight into diferent gene regulation mechanisms. However, to date it remains challenging to understand how combinations of transcription factors together with epigenetic events control cell‑type specifc gene expression. We have developed the AnnoMiner web‑server, an innovative and fexible tool to annotate and integrate epigenetic, and transcription factor occupancy data. First, AnnoMiner annotates user‑provided peaks with gene features. Second, AnnoMiner can integrate genome binding data from two diferent transcriptional regulators together with gene features. Third, AnnoMiner ofers to explore the transcriptional deregulation of genes nearby, or within a specifed genomic region surrounding a user‑provided peak. AnnoMiner’s fourth function performs transcription factor or histone modifcation enrichment analysis for user‑provided gene lists by utilizing hundreds of public, high‑quality datasets from ENCODE for the model organisms human, mouse, Drosophila and C. elegans. Thus, AnnoMiner can predict transcriptional regulators for a studied
    [Show full text]
  • The Physical Mechanisms of Drosophila Gastrulation: Mesoderm and Endoderm Invagination
    | FLYBOOK DEVELOPMENT AND GROWTH The Physical Mechanisms of Drosophila Gastrulation: Mesoderm and Endoderm Invagination Adam C. Martin1 Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142 ORCID ID: 0000-0001-8060-2607 (A.C.M.) ABSTRACT A critical juncture in early development is the partitioning of cells that will adopt different fates into three germ layers: the ectoderm, the mesoderm, and the endoderm. This step is achieved through the internalization of specified cells from the outermost surface layer, through a process called gastrulation. In Drosophila, gastrulation is achieved through cell shape changes (i.e., apical constriction) that change tissue curvature and lead to the folding of a surface epithelium. Folding of embryonic tissue results in mesoderm and endoderm invagination, not as individual cells, but as collective tissue units. The tractability of Drosophila as a model system is best exemplified by how much we know about Drosophila gastrulation, from the signals that pattern the embryo to the molecular components that generate force, and how these components are organized to promote cell and tissue shape changes. For mesoderm invagination, graded signaling by the morphogen, Spätzle, sets up a gradient in transcriptional activity that leads to the expression of a secreted ligand (Folded gastrulation) and a transmembrane protein (T48). Together with the GPCR Mist, which is expressed in the mesoderm, and the GPCR Smog, which is expressed uniformly, these signals activate heterotrimeric G-protein and small Rho-family G-protein signaling to promote apical contractility and changes in cell and tissue shape. A notable feature of this signaling pathway is its intricate organization in both space and time.
    [Show full text]