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Identification and Characterization of Developmentally IDENTIFICATION AND CHARACTERIZATION OF DEVELOPMENTALLY REGULATED COMPONENTS OF THE STRESS AXIS IN PETROMYZON MARINUS A Thesis Submitted to the Faculty of Graduate Studies and Research In Partial Fulfillment of the Requirements For the Degree of Master of Science in Biology University of Regina by Matthew Joel Endsin Regina, Saskatchewan January, 2013 Copyright 2013: M. Endsin UNIVERSITY OF REGINA FACULTY OF GRADUATE STUDIES AND RESEARCH SUPERVISORY AND EXAMINING COMMITTEE Matthew Joel Endsin, candidate for the degree of Master of Science in Biology, has presented a thesis titled, Identification and Characterization of Developmentally Regulated Components of the Stress Axis in Petromyzon Marinus, in an oral examination held on December 19, 2012. The following committee members have found the thesis acceptable in form and content, and that the candidate demonstrated satisfactory knowledge of the subject material. External Examiner: Dr. Mohan Babu, Department of Biochemistry Supervisor: Dr. Richard Manzon, Department of Biology Committee Member: Dr. Josef Buttigieg, Department of Biology Chair of Defense: Dr. Heather Ryan, Faculty of Education ABSTRACT Genes resembling elements of the Corticotropin releasing hormone (CRH) receptor-ligand system (CRH system) have been identified in invertebrate species and suggest the CRH system has existed, in some form, for approximately a billion years. It is theorized that vertebrates inherited components of the CRH system from an invertebrate ancestor. The association of the CRH system with the stress response, however, is specific to vertebrate species and theorized to have accompanied the development of hypothalamic pituitary (HP) axes, specifically the HP interrenal (HPI) axis in fish. A functional HPI axis has recently been suggested in the lamprey species Petromyzon marinus, a member of the ancient vertebrate superclass agnatha, by identification of pituitary and inter-renal components corticotrophin (ACTH) and 11- deoxycortisol respectively. This study, however, is the first to identify the hypothalamic components, specifically the CRH system, of the HPI. In P. marinus the expression of six CRH system genes, including three hormones, CRH A, CRH B and UCN III-like; two receptors, CRH Rα and CRH Rβ; and a binding protein, CRH BP, are identified by PCR and in silico methodologies. Analysis of the P. marinus CRH system genes appear to support the occurance of the Agnathan superclass prior to a theorized second vertebrate whole genome duplication (WGD) event. This is supported by the P. marinus CRH hormones appearing to represent two of the four vertebrate CRH family paralogues; CRH A and B both being orthologous to vertebrate CRH, and UCN III-like being orthologous to vertebrate UCN III. Additionally, neither CRH Rα nor CRH Rβ, while identified as distinct from one another and related to other vertebrate receptors, were phylogenetically indistinguishable as either i type 1 or 2. This suggests, the two P. marinus CRH receptor genes identified appear to have arisen out of a lamprey specific duplication event they diverged separately from the formation of the type 1 and type 2 receptors. The P. marinus CRH BP deduced amino acid sequence was found to contain regions highly conserved and functionally significant in other vertebrates as well as invertebrate species, and occupies a unique phylogenetic branch. Expression of these genes in brain, gill, liver, kidney as measured by reverse transcription quantitative PCR (RT qPCR) over the life history of P. marinus (including pre-metamorphic larvae, each of the seven stages of metamorphosis, and juvenile parasites) indicated significant variation in gene expression both between tissues and through the life history. Differences in expression were observed for each P. marinus CRH system gene and correlate with significant physiological changes occurring in the developing P. marinus. Some of these include increases in Na+/K+ -ATPase activity in the gill, possibly relating to salt water tolerance, and lipogenic and lipolytic metabolic phases in the kidney and liver. Interestingly, comparatively high expression levels of CRH A, CRH B and CRH Rβ were observed in the JP gonad relative to other JP organs. This suggests these genes may have a paracrine role in this organ, possibly by local regulation of sex steroids, similar to that observed in mice and humans. Interestingly, CRH system mRNA expression did not vary in response to multiple successive acute stressors, including dewatering and salt water exposure, over a 24 hour period as measured by RT qPCR. This suggests that P. marinus CRH system genes may not respond to such stressors at the level of mRNA expression. Collectively, these data indicate that lamprey contain all necessary components of a complete HPI axis, and that the CRH system likely plays an important role in the normal development. ii ACKNOWLEDGMENTS I would like to firstly thank my supervisor, Dr. Richard Manzon, for the exceptional opportunities I have undertaken and experienced over the last few years on this project. Over the course of this project he has regularly offered guidance, support and, perhaps most importantly, a fresh pot of coffee. I believe the camaraderie and cohesiveness of the students in the Manzon lab is a reflection of the attitude of Dr. Manzon, and has made the lab somewhere I have looked forward to coming into every day. On that note, I would like to acknowledge the members of ‘Team Manzon’, both past and present, which I now have the privilege of calling my friends. Specifically, Amy Tetlock, who assisted with animal collection and care, and fellow graduate student ‘Texas’ Dan Stefanovic, who shared my passion for football, fishing and biology and offered technical advice throughout my project. I would also like to acknowledge April Sefton, Rebecca Eberts, and Adam Vantomme who all aided, to a varying degree, with animal collection, sample prep and animal care. I would like to acknowledge the work of Odette Allenby, Tara Hicks and Dr. Lori Manzon, who provided the initial sequence data on the lamprey CRH system prior to my arrival as a Masters student. This work has been made possible by grants from the Natural Sciences and Engineering Research Council of Canada and the Canada Foundation of Innovation to Dr. Richard G. Manzon. Matthew Endsin was supported in part by graduate scholarships and awards from both the Faculty of Graduate Studies and Research and the department of Biology at University of Regina. iii TABLE OF CONTENTS ABSTRACT .......................................................................................................................................... i ACKNOWLEDGMENTS ..................................................................................................................... iii TABLE OF CONTENTS....................................................................................................................... iv LIST OF FIGURES .............................................................................................................................. vi LIST OF TABLES ................................................................................................................................ vi LIST OF ABBREVIATIONS ............................................................................................................... viii 1. INTRODUCTION ........................................................................................................................ 2 1.1 The Life History of P. marinus ................................................................................................ 2 1.2 Stress ...................................................................................................................................... 4 1.3 The Corticotropin Releasing Hormone family ........................................................................ 6 1.4 The CRH receptors ............................................................................................................... 13 1.5 The CRH Binding Protein ...................................................................................................... 17 1.6 Objectives ...................................................................................................................... 20 2. MATERIALS AND METHODS ....................................................................................................... 22 2.1 Animals ................................................................................................................................. 22 2.2 Primer design ....................................................................................................................... 23 2.3 Identification and Cloning of Transcripts ............................................................................. 24 2.4 In silico analysis .................................................................................................................... 28 2.5 Phylogenetic analysis ........................................................................................................... 29 2.6 Stress Experiment ................................................................................................................ 29 2.7 Developmental and tissue distribution ................................................................................ 30 2.8 Data and statistical analysis ................................................................................................. 35
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