DOCSLIB.ORG

02Main.Pdf (3.115Mb)

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
02Main.Pdf (3.115Mb) Hox Transcription Factors: Their Involvement in Human Cancer Cells and In Vitro Functional Specificity Author Svingen, Terje Published 2005 Thesis Type Thesis (PhD Doctorate) School School of Biomolecular and Physical Sciences DOI https://doi.org/10.25904/1912/1181 Copyright Statement The author owns the copyright in this thesis, unless stated otherwise. Downloaded from http://hdl.handle.net/10072/365774 Griffith Research Online https://research-repository.griffith.edu.au CHAPTER 1 General Introduction CHAPTER 1 General Introduction 1 CHAPTER 1 General Introduction 1.1 GENERAL INTRODUCTION Homeobox genes are regulatory genes encoding small proteins that act as transcription factors during normal development (Gehring and Hiromi 1986) and were first identified in the fruit fly Drosophila melanogaster (Lewis 1978). A common feature of these proteins is the presence of a highly conserved 61-amino acid motif, the homeodomain that enables homeodomain proteins to bind to DNA at specifically recognised binding sites and transcriptionally activate their target genes, as extensively reviewed (Levine and Hoey 1988; Scott et al. 1989; McGinnis and Krumlauf 1992). At present, a large number of homeobox genes have been characterised, now comprising an extensive super-family of regulatory genes with members found in all animal species. There is a large catalogue of divergent homeobox sub-families, of which the best characterised and most extensively studied is the HOX/Hox-family. In mammalian species, there are 39 Hox genes organised in four clusters located on four different chromosomes in the genome (Scott 1992). They are structural and functional homologs of the Drosophila homeotic complexes (Hom-C), and are thought to have arisen through the combination of cis-amplification and trans-duplication of the Drosophila bithorax and antennapedia complexes during separate evolutionary events (Krumlauf 1994; Meyer 1996). As the Hox proteins were identified quite early as regulatory transcription factors with DNA-specific recognition facilitated via the conserved homeodomain, much effort has gone into trying to elucidate the exact mechanisms by which the Hox proteins gain their functional specificity and where in the regulatory hierarchy they exert their effect. Even so, although much has been learned, there are still large gaps in the puzzle that eventually will draw out a picture enabling us to fully appreciate the intricate control mechanisms governed by the Hox proteins. As the homeodomain-containing transcription factors were found to be key regulators of embryogenesis and normal development, researchers considered that potentially these regulatory proteins could also be involved in various aspects of cancer development. Although the underlying cellular mechanisms that destine a normal cell to become neoplastic are highly variable, collective principles governing malignant growth are distinguishable. Amongst these are self-sufficiency in growth 2 CHAPTER 1 General Introduction signals, sustained angiogenesis, tissue invasion and evasion of apoptosis (Hanahan and Weinberg 2000). Since the physiological processes governing oncogenesis across a large number of cancer cell genotypes are similar, it has been postulated that the large and diverse collection of cancer-associated genes might be tied to the operation of a small group of regulatory circuits. Furthermore, as the molecular mechanisms involved in carcinogenesis deal with the acquisition, regulation and maintenance of cell identity, many researchers have proposed regulatory proteins involved in embryogenesis and the maintenance of normal cells to be potential candidates as oncogenic regulators (Castronovo et al. 1994; Ford 1998; Cillo et al. 1999; Hanahan and Weinberg 2000; Cillo et al. 2001). Hence, the homeobox genes became a focal point for several research groups trying to elucidate the genetic control of carcinogenesis. Not only were the homeodomain transcription factors quickly being characterised as major players throughout embryogenesis, but research also strongly suggested that the homeobox gene families were key regulators of many biological processes in adult eukaryotic cells. Among these processes are cell-cell and cell-extracellular matrix interactions (Srebow et al. 1998), capillary morphogenesis and angiogenesis (Boudreau et al. 1997; Myers et al. 2000), cell cycle control (Ford et al. 1998), and cell growth and differentiation (Magli et al. 1991). The present study seeks to further investigate the potential involvement of homeodomain-containing transcription factors in human carcinogenesis. Due to the vast number of homeobox genes present in the human genome – estimated to 0.1- 0.2% of the whole vertebrate genome (Stein et al. 1996) – the class I homeobox, or Hox genes, will be the main focus, with subtle references to related homeobox gene families. As will become evident, other aspects of Hox transcriptional and functional specificity in the non-malignant cellular environment will form an equally important part of this thesis. There is still much to be elucidated regarding these normal regulatory principles however, if the potential involvement of Hox genes in carcinogenesis is to be unravelled. 3 CHAPTER 1 General Introduction 1.2 THE HOX TRANSCRIPTION FACTORS 1.2.1 Homeotic Genes and the Homeodomain Although the early work of Lewis (1978) allowed for the characterization of key genetic loci controlling Drosophila development, including homeotic genes, the actual homeobox was to be discovered some years later (McGinnis et al. 1984; Scott and Weiner 1984). The homeobox is a highly conserved 183-bp DNA sequence that encodes a 61-amino acid domain, termed the homeodomain, and was originally characterised by nuclear magnetic resonance (NMR) spectroscopy (Qian et al. 1989; Billeter et al. 1990) on a 68 amino acid residue Antp homeodomain expressed in E. coli (Muller et al. 1988). The tertiary structure of the homeodomain is a so-called helix-turn-helix motif (Figure 1.1) that enables homeodomain proteins to bind to DNA at specifically recognised binding sites (Figure 1.2) and transcriptionally activate their target genes (Wuthrich et al. 1992; Latchman 1995). FIGURE 1.1: The Homeodomain Tertiary Structure. Homeodomain from the Drosophila Antennapedia protein. The three helices making up the Drosophila Antennapedia homeodomain are prototypic for all homeobox proteins, serving as the core structure even for divergent homeobox families. Source: PDF file from (RCSB 2000), with image produced with Swiss PDB viewer: (Guex et al. 2004). 4 CHAPTER 1 General Introduction FIGURE 1.2: Homeodomain Protein Segment Bound to DNA. The third helix with its acidic tail resides in the major groove of the DNA duplex, making most of the recognition contacts with the DNA. The N-terminal flexible arm and the loop between helix 1 and helix 2 also make important contacts with the DNA duplex. Source: (ExPASy 2000). In addition to the homeodomain, the homeobox genes also encode other highly conserved structures (Figure 1.3). The homeodomain itself ends with an acidic tail, with an as yet undetermined structure. Furthermore, many homeodomain proteins, albeit not all, contain a highly conserved pentapeptide (IYPWM), the homeopeptide, just upstream from the homeodomain. Finally, homeobox proteins contain a conserved amino-terminal region followed by a variable region, usually rich in alanine, serine, glycine, proline or glutamine (Castronovo et al. 1994). 5 CHAPTER 1 General Introduction FIGURE 1.3: Schematic Representation of a Prototypic Homeodomain Protein. The main conserved regions of a prototypic homeodomain protein (Antp/Hox). The homeodomain is further highlighted with the three alpha helices. The prototypic Hox gene encoding this structure generally contains one intron between the homeopeptide and the homeodomain. Source: (Castronovo et al. 1994) The homeodomain proteins have been shown to be key regulators of embryonic development and differentiation (Marx 1992) and they are found in all animals tested to date, and even in many plants (Ulijaszek et al. 1998). There are numerous classes of homeobox genes and novel isolates are still being identified, adding to the list of more than 340 known homeodomain sequences (Gehring et al. 1994). It has been estimated that as much as 0.1% of the vertebrate genome is accounted for by homeobox genes, and by 1996, 170 different homeobox genes had already been cloned from vertebrate genomes (Stein et al. 1996). Also after the release of the human genome, extensive analyses has revealed that the homeobox indeed seems to be represented at this 0.1% level (Tupler et al. 2001), and there are still puzzling new discoveries being made, as for instance the discovery of a Hox14 paralog gene in horn sharks and coelacanths (Ferrier 2004; Powers and Amemiya 2004). As the homeobox genes were first discovered in the fruit fly Drosophila melanogaster and much of our understanding of these important transcription factors originates from these early studies, a brief discussion on the Drosophila homeotic genes will follow, before focusing more directly on the vertebrate homologs. 6 CHAPTER 1 General Introduction 1.2.2 The Homeotic Genes of Drosophila melanogaster As already mentioned, the homeobox genes were first discovered in Drosophila, with the observations that mutations in such genes often resulted in homeotic transformations of the body plan. An extensive collection of mutations were quickly assembled (Lewis 1978; Kaufman et al. 1980), and as these mutations resulted
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]
  • Alternative Splicing Modulates Ubx Protein Function in Drosophila Melanogaster
    Copyright Ó 2010 by the Genetics Society of America DOI: 10.1534/genetics.109.112086 Alternative Splicing Modulates Ubx Protein Function in Drosophila melanogaster Hilary C. Reed,* Tim Hoare,† Stefan Thomsen,‡ Thomas A. Weaver,† Robert A. H. White,† Michael Akam* and Claudio R. Alonso‡,1 *Department of Zoology, University of Cambridge, Cambridge CB2 3EJ, United Kingdom, †Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, United Kingdom and ‡School of Life Sciences, University of Sussex, Brighton BN1 9QG, United Kingdom Manuscript received November 13, 2009 Accepted for publication December 17, 2009 ABSTRACT The Drosophila Hox gene Ultrabithorax (Ubx) produces a family of protein isoforms through alternative splicing. Isoforms differ from one another by the presence of optional segments—encoded by individual exons—that modify the distance between the homeodomain and a cofactor-interaction module termed the ‘‘YPWM’’ motif. To investigate the functional implications of Ubx alternative splicing, here we analyze the in vivo effects of the individual Ubx isoforms on the activation of a natural Ubx molecular target, the decapentaplegic (dpp) gene, within the embryonic mesoderm. These experiments show that the Ubx isoforms differ in their abilities to activate dpp in mesodermal tissues during embryogenesis. Furthermore, using a Ubx mutant that reduces the full Ubx protein repertoire to just one single isoform, we obtain specific anomalies affecting the patterning of anterior abdominal muscles, demonstrating that Ubx isoforms are not functionally interchangeable during embryonic mesoderm development. Finally, a series of experiments in vitro reveals that Ubx isoforms also vary in their capacity to bind DNA in presence of the cofactor Extradenticle (Exd).
    [Show full text]
  • HOX CLUSTER INTERGENIC SEQUENCE EVOLUTION by JEREMY DON RAINCROW a Dissertation Submitted to the Graduate School-New Brunswick R
    HOX CLUSTER INTERGENIC SEQUENCE EVOLUTION By JEREMY DON RAINCROW A Dissertation submitted to the Graduate School-New Brunswick Rutgers, The State University of New Jersey and The Graduate School of Biomedical Sciences University of Medicine and Dentistry of New Jersey in partial fulfillment of the requirements for the degree of Doctor of Philosophy Graduate Program in Cell and Developmental Biology written under the direction of Chi-hua Chiu and approved by ______________________________________________ ______________________________________________ ______________________________________________ ______________________________________________ New Brunswick, New Jersey October 2010 ABSTRACT OF THE DISSERTATION HOX GENE CLUSTER INTERGENIC SEQUENCE EVOLUTION by JEREMY DON RAINCROW Dissertation Director: Chi-hua Chiu The Hox gene cluster system is highly conserved among jawed-vertebrates. Specifically, the coding region of Hox genes along with their spacing and occurrence is highly conserved throughout gnathostomes. The intergenic regions of these clusters however are more variable. During the construction of a comprehensive non-coding sequence database we discovered that the intergenic sequences appear to also be highly conserved among cartilaginous and lobe-finned fishes, but much more diverged and dynamic in the ray-finned fishes. Starting at the base of the Actinopterygii a turnover of otherwise highly conserved non-coding sequences begins. This turnover is extended well into the derived ray-finned fish clade, Teleostei. Evidence from our population genetic study suggests this turnover, which appears to be due mainly to loosened constraints at the macro-evolutionary level, is highlighted by evidence of strong positive selection acting at the micro-evolutionary level. During the construction of the non-coding sequence database we also discovered that along with evidence of both relaxed constraints and positive selection emerges a pattern of transposable elements found within the Hox gene cluster system.
    [Show full text]
  • Homeotic Gene Action in Embryonic Brain Development of Drosophila
    Development 125, 1579-1589 (1998) 1579 Printed in Great Britain © The Company of Biologists Limited 1998 DEV1254 Homeotic gene action in embryonic brain development of Drosophila Frank Hirth, Beate Hartmann and Heinrich Reichert* Institute of Zoology, University of Basel, Rheinsprung 9, CH-4051 Basel, Switzerland *Author for correspondence (e-mail: reichert@ubaclu.unibas.ch) Accepted 18 February; published on WWW 1 April 1998 SUMMARY Studies in vertebrates show that homeotic genes are absence of labial, mutant cells are generated and positioned involved in axial patterning and in specifying segmental correctly in the brain, but these cells do not extend axons. identity of the embryonic hindbrain and spinal cord. To Additionally, extending axons of neighboring wild-type gain further insights into homeotic gene action during CNS neurons stop at the mutant domains or project ectopically, development, we here characterize the role of the homeotic and defective commissural and longitudinal pathways genes in embryonic brain development of Drosophila. We result. Immunocytochemical analysis demonstrates that first use neuroanatomical techniques to map the entire cells in the mutant domains do not express neuronal anteroposterior order of homeotic gene expression in the markers, indicating a complete lack of neuronal identity. Drosophila CNS, and demonstrate that this order is An alternative glial identity is not adopted by these mutant virtually identical in the CNS of Drosophila and mammals. cells. Comparable effects are seen in Deformed mutants but We then carry out a genetic analysis of the labial gene in not in other homeotic gene mutants. Our findings embryonic brain development. Our analysis shows that demonstrate that the action of the homeotic genes labial loss-of-function mutation and ubiquitous overexpression of and Deformed are required for neuronal differentiation in labial results in ectopic expression of neighboring the developing brain of Drosophila.
    [Show full text]
  • Mechanisms of Specificity for Hox Factor Activity
    Journal of Developmental Biology Review Mechanisms of Specificity for Hox Factor Activity Arya Zandvakili 1,2 and Brian Gebelein 3,* 1 Molecular and Developmental Biology Graduate Program, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA 2 Medical-Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; zandvaaa@mail.uc.edu 3 Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA * Correspondence: brian.gebelein@cchmc.org; Tel.: +1-513-636-3366 Academic Editors: Vincenzo Zappavigna and Simon J. Conway Received: 5 April 2016; Accepted: 4 May 2016; Published: 9 May 2016 Abstract: Metazoans encode clusters of paralogous Hox genes that are critical for proper development of the body plan. However, there are a number of unresolved issues regarding how paralogous Hox factors achieve specificity to control distinct cell fates. First, how do Hox paralogs, which have very similar DNA binding preferences in vitro, drive different transcriptional programs in vivo? Second, the number of potential Hox binding sites within the genome is vast compared to the number of sites bound. Hence, what determines where in the genome Hox factors bind? Third, what determines whether a Hox factor will activate or repress a specific target gene? Here, we review the current evidence that is beginning to shed light onto these questions. In particular, we highlight how cooperative interactions with other transcription factors (especially PBC and HMP proteins) and the sequences of cis-regulatory modules provide a basis for the mechanisms of Hox specificity. We conclude by integrating a number of the concepts described throughout the review in a case study of a highly interrogated Drosophila cis-regulatory module named “The Distal-less Conserved Regulatory Element” (DCRE).
    [Show full text]
  • Engrailed Homeoproteins in Visual System Development
    Cell. Mol. Life Sci. (2015) 72:1433–1445 DOI 10.1007/s00018-014-1776-z Cellular and Molecular Life Sciences REVIEW Engrailed homeoproteins in visual system development Andrea Wizenmann • Olivier Stettler • Kenneth L. Moya Received: 28 July 2014 / Revised: 31 October 2014 / Accepted: 6 November 2014 / Published online: 29 November 2014 Ó The Author(s) 2014. This article is published with open access at Springerlink.com Abstract Engrailed is a homeoprotein transcription Keywords Visual system Á Retina Á Tectum Á factor. This family of transcription factors is characterized Sensory map Á Homeoprotein Á Engrailed by their DNA-binding homeodomain and some members, including Engrailed, can transfer between cells and reg- ulate protein translation in addition to gene transcription. Introduction Engrailed is intimately involved in the development of the vertebrate visual system. Early expression of Engrailed in Since the discovery of homeobox genes [1, 2] there has dorsal mesencephalon contributes to the development and been accumulating evidence from all multi-cellular organization of a visual structure, the optic tectum/supe- organisms that these genes play key roles in determining rior colliculus. This structure is an important target for positional information. These genes encode homeoprotein retinal ganglion cell axons that carry visual information transcription factors that regulate the expression of down- from the retina. Engrailed regulates the expression of stream genes necessary at all developmental stages, Ephrin axon guidance cues in the tectum/superior col- including lineage determination, cell migration, cell dif- liculus. More recently it has been reported that Engrailed ferentiation, and tissue formation. Some homeoproteins are itself acts as an axon guidance cue in synergy with the also able to regulate protein translation and cell-to-cell Ephrin system and is proposed to enhance retinal topo- signaling.
    [Show full text]
  • Characterisation of HPC3, a New Human Polycomb Group Protein
    Characterisation of HPC3, A NEW HUMAN POLYCOMB GROUP PROTEIN Julia I. Bardos Thesis presented for the degree of Doctor of Philosophy from the University of London August 2001 Molecular Structure and Function Laboratory Imperial Cancer Research Fund 44 Lincoln’s Inn Fields London WC2A 3PX ProQuest Number: U643553 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest. ProQuest U643553 Published by ProQuest LLC(2016). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 A b s t r a c t A b str a c t Polycomb Group (PcG) proteins are a conserved group of transcriptional repressors, mainly known for their role in stably maintaining the repressed state of homeotic and Hox genes, after their expression patterns have been established early in embryonic development. Thus, the Polycomb Group constitutes an important part of a cellular transcriptional memory system. Loss of PcG function leads to homeotic transformations in Drosophila and corresponding shifts in Hox gene expression in vertebrates. PcG proteins form multiprotein complexes of varying composition that associate with chromatin, and it has been postulated that they achieve gene silencing by altering higher order chromatin structure.
    [Show full text]
  • Evolving Pathways Key Themes in Evolutionary Developmental Biology
    Evolving Pathways Key Themes in Evolutionary Developmental Biology Evolutionary developmental biology, or ‘evo-devo’, is the study of the relationship between evolution and development. Dealing specifically with the generative mechanisms of organismal form, evo-devo goes straight to the core of the developmental origin of variation, the raw material on which natural selection (and random drift) can work. Evolving Pathways responds to the growing volume of data in this field, with its potential to answer fundamental questions in biology, by fuelling debate through contributions that represent a diversity of approaches. Topics range from developmental genetics to comparative morphology of animals and plants alike, including palaeontology. Researchers and graduate students will find this book a valuable overview of current research as we begin to fill a major gap in our perception of evolutionary change. ALESSANDRO MINELLI is currently Professor of Zoology at the University of Padova, Italy. An honorary fellow of the Royal Entomological Society, he was a founding member and Vice-President of the European Society for Evolutionary Biology. He has served as President of the International Commission on Zoological Nomenclature, and is on the editorial board of multiple learned journals, including Evolution & Development. He is the author of The Development of Animal Form (2003). GIUSEPPE FUSCO is Assistant Professor of Zoology at the University of Padova, Italy, where he teaches evolutionary biology. His main research work is in the morphological
    [Show full text]
  • Homeotic Transformations and Limb Defects in Hox All Mutant Mice
    Downloaded from genesdev.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press Homeotic transformations and limb defects in Hox All mutant mice Kersten M. Small and S. Steven Potter ~ Division of Basic Science Research, Children's Hospital Research Foundation, Cincinnati, Ohio 45229 USA Hox All is one of the expanded set of vertebrate homeo box (Hox) genes with similarities to the Drosophila homeotic gene, Abdominal-B (Abd-B). These Abd-B-type Hox genes have been shown to be expressed in the most caudal regions of the developing vertebrate embryo and in overlapping domains within the developing limbs, suggesting that these genes play important roles in pattern formation in both appendicular and axial regions of the body. In this report whole-mount in situ hybridization in mouse embryos gave a precise description of Hox All gene expression in the developing limbs and in the axial domain of the developing body. In addition, we generated a targeted mutation in Hox All and characterized the resulting phenotype to begin to dissect developmental functions of the Abd-B subfamily of Hox genes. Hox All mutant mice exhibited double homeotic transformations, with the thirteenth thoracic segment posteriorized to form an additional first lumbar vertebra and with the sacral region anteriorized, generating yet another lumbar segment. Furthermore, skeletal malformations were observed in both forelimbs and hindlimbs. In mutant forelimbs, the ulna and radius were misshapen, the pisiform and triangular carpal bones were fused, and abnormal sesamoid bone development occurred. In mutant hindlimbs the tibia and fibula were joined incorrectly and malformed at their distal ends.
    [Show full text]
  • Modulation of AP and DV Signaling Pathways by the Homeotic Gene Ultrabithorax During Haltere Development in Drosophila ⁎ Prasad Mohit , Kalpana Makhijani, M.B
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Developmental Biology 291 (2006) 356–367 www.elsevier.com/locate/ydbio Genomes & Developmental Control Modulation of AP and DV signaling pathways by the homeotic gene Ultrabithorax during haltere development in Drosophila ⁎ Prasad Mohit , Kalpana Makhijani, M.B. Madhavi, V. Bharathi, Ashish Lal, Gururaj Sirdesai, ⁎ V. Ram Reddy, Palaparthi Ramesh, Ramakrishnan Kannan, Jyotsna Dhawan, L.S. Shashidhara Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500 007, India Received for publication 16 August 2005; revised 5 December 2005; accepted 6 December 2005 Available online 18 January 2006 Abstract Suppression of wing fate and specification of haltere fate in Drosophila by the homeotic gene Ultrabithorax is a classical example of Hox regulation of serial homology (Lewis, E.B. 1978. Nature 276, 565–570) and has served as a paradigm for understanding homeotic gene function. We have used DNA microarray analyses to identify potential targets of Ultrabithorax function during haltere specification. Expression patterns of 18 validated target genes and functional analyses of a subset of these genes suggest that down-regulation of both anterior–posterior and dorso- ventral signaling is critical for haltere fate specification. This is further confirmed by the observation that combined over-expression of Decapentaplegic and Vestigial is sufficient to override the effect of Ubx and cause dramatic haltere-to-wing transformations. Our results also demonstrate that analysis of the differential development of wing and haltere is a good assay system to identify novel regulators of key signaling pathways.
    [Show full text]
  • Maximisation Principles in Evolutionary Biology
    MAXIMISATION PRINCIPLES IN EVOLUTIONARY BIOLOGY A. W. F. Edwards 1 INTRODUCTION Maximisation principles in evolutionary biology (or, more properly, extremum principles, so as to include minimisation as well) fall into two classes — those that seek to explain evolutionary change as a process that maximises fitness in some sense, and those that seek to reconstruct evolutionary history by adopting the phylogenetic tree that minimises the total amount of evolutionary change. Both types have their parallels in the physical sciences, from which they originally drew their inspiration. There are important differences, however, and the naive introduction of extremum principles into biology has tended to obscure rather than clarify the underlying processes and estimation procedures, often leading to controversy. To understand the difficulties it is necessary first to note the use of extremum principles in physics. 2 EXTREMUM PRINCIPLES IN PHYSICS Extremum principles exert a peculiar fascination in science. The classic physics example is from optics, where Fermat in the 17th century established that when a ray of light passes from a point in one medium through a plane interface to a point in another medium with a different refractive index its route is the one which minimises the time it takes for the light to travel. That is, on various assumptions about the speed of light in the different media, he showed that this solution corresponded to Snel’s existing Sine Law of refraction. As a matter of fact modern books on optics find it necessary to frame Fermat’s principle rather differently, not using the notion of a minimum at all, but the point for us is that in its original form it solves at least some optical path problems by minimisation.
    [Show full text]
  • Expression Patterns of Anterior Hox Genes in the Polychaete
    Developmental Biology 217, 333–351 (2000) doi:10.1006/dbio.1999.9541, available online at http://www.idealibrary.com on View metadata, citation and similar papers at core.ac.uk brought to you by CORE Expression Patterns of Anterior Hox Genes provided by Elsevier - Publisher Connector in the Polychaete Chaetopterus: Correlation with Morphological Boundaries Steven Q. Irvine*,1 and Mark Q. Martindale*,†,2 *Committee on Evolutionary Biology, and †Department of Organismal Biology and Anatomy, University of Chicago, 1027 East 57th Street, Chicago, Illinois 60637 Expression patterns for five Hox genes were examined by whole-mount in situ hybridization in larvae of Chaetopterus, a polychaete annelid with a tagmatized axial body plan. Phylogenetic analysis demonstrates that these genes are orthologs of the Drosophila genes labial, proboscipedia, zen, Deformed, and Sex combs reduced and are termed CH-Hox1, CH-Hox2, CH-Hox3, CH-Hox4, and CH-Hox5, respectively. Expression studies reveal a biphasic expression pattern. In early larval stages, well before any indications of segmental organization exist, a novel pattern of expression in bilateral posterior proliferating cell populations, corresponding to the teloblasts, was detected for each of the genes, with CH-Hox1 and CH-Hox2 expressed before the remaining three. In middle larval stages, all five genes are expressed in bilateral strips along the ventral midline, corresponding with the developing ventral nerve cord. In addition, CH-Hox1 and CH-Hox2 show strong expression at the foregut-midgut boundary. By late larval stages the expression is generally confined to the ventral CNS and ectoderm of the anterior parapodia. Anterior boundaries of expression are “colinear,” at later larval stages, with CH-Hox2 expressed most rostrally, in the first segment, and anterior expression boundaries for CH-Hox1, CH-Hox3, CH-Hox4, and CH-Hox5 in segments 2, 3, 4, and 5, respectively.
    [Show full text]