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TR056/PG1007 Lecture 7 Regula5on of Pa9erning Dr. Neil Docherty My Teaching Objec/ves • To emphasise that the body plan should be considered in terms of the three axes • To relate the role of model systems in the story of identifying the genes controlling anterior-posterior patterning (A-P) in the embryo • To describe the concept of colinearity with regard to HOX gene expression patterns and illustrate how exogenous retinoids may disrupt this pattern • To briefly consider the main concepts of D-V and L-R patterning Complexity of Body Plan Gametes Zygote Diverse final body plans all pass through these stages under the control of patterning genes which are fundamentally conserved through the evolutionary tree Blastocyst Embryo THE 3 AXES 1. Anterior-posterior/head-tail (cranial-caudal) 2. Dorso-ventral 3. Left-right (bilateral body plan chordata) Foetus The Body Axes R L Cr Ca V D Establishment of these axes depends on site specific gene expression patterns Origin of Our Understanding of Patterning Along The Anterior-Posterior Axis The master regulators of patterning along this axis are the HOX genes (transcription factors) The story of the elucidation of the role of these genes begins with the original description of the phenomenon of homeosis “The essential phenomenon is not that there has merely been a change, but that something has changed into the likeness of something else” William Bateson 1894 Drosophila Melanogaster and the Discovery of Genes Controlling Homeo/c Transi/on The Nobel Prize in Physiology or Medicine 1995 -Edward B. Lewis -Christiane Nüsslein-Volhard -Eric F. Wieschaus "for their discoveries concerning the genetic control of early embryonic development". Lewis identified that mutations in a gene complex on chromosome 3 were responsible for homeotic duplication of wings in mutant flies HOX-‐Genes • In mammals HOX genes arranged in 4 sets of 13 Location of Lewis’s Across 4 chromosomes (7-A 17-B 12-C D-2) wing mutation • Each gene includes a Homeobox consensus • This sequence codes for a homeodomain (60a/a) • The homeodomain binds to a TAAT…. enhancer on regulatory regions of target genes Paralogous groups 3’ early 5’ late Expression of HOX Genes Along Dorsal Axis Note that HOX expression patterns show sharp boundaries cranially and graded boundaries caudally This leads to different doses of HOX genes at given levels and the staggered complete absence of individual HOX genes at the cranial end Evidence that a HOX Code Causes Axis Specifica/on 1. Gene knockout experiments 2. Comparative Anatomy 3. Retinoic Acid Teratogenesis Retinoic Acid Teratogenesis Retinoic acid is normally produced in the embryo (node) and constitutes one of the elements controlling HOX gene expression Excess maternally derived retinol can be metabolised In the embryo to produce excess retinoic acid This interferes with the gradients of retinoic acid along the A-P axis This can lead to homeotic transitions Retinoic Acid-Regulation of HOX Gene Expression Left-Right Asymmetry Consider the fact that overall external symmetry of the body is not matched in the visceral organs How can this be? The answer in part may be due to cilia and the asymmetric accumulation of nodal protein secreted from the primitive node Mutations in key cilial motor proteins produce situs inversus as well as respiratory disease in Kartagener’s Syndrome Bilateral Assymetry The Dorsal-Ventral Axis This axis is specified by the separation of the inner cell mass into Embryonic and Abembryonic regions This develops perpendicular to the animal-vegetal pole of the fertilised egg D-V specifc gene expression then is maintained by the effect of signals from the notochord on the overlying ectoderm Notochord derived signals Today’s Learning Objec/ves Your learning from today should focus on being able to; 1) Describe the body plan in terms of the three axes 2) Relate how the phenomena of segmentation and homeosis in model systems helped explain anterior-posterior patterning (A-P) in the human embryo 3) Explain the concept of colinearity with regard to HOX gene expression patterns and illustrate how endogenous retinoids control this and how exogenous retinoids therefore act as teratogens.