Advances in Experimental Medicine and Biology 886 Dagmar Wilhelm Pascal Bernard Editors Non-coding RNA and the Reproductive System Advances in Experimental Medicine and Biology Volume 886 Editorial Board Irun R. Cohen , The Weizmann Institute of Science , Rehovot , Israel N.S. Abel Lajtha , Kline Institute for Psychiatric Research , Orangeburg , NY , USA John D. Lambris , University of Pennsylvania , Philadelphia , PA , USA Rodolfo Paoletti , University of Milan , Milan , Italy More information about this series at http://www.springer.com/series/5584 Dagmar Wilhelm • Pascal Bernard Editors Non-coding RNA and the Reproductive System Editors Dagmar Wilhelm Pascal Bernard Department of Anatomy School of BioSciences and Neuroscience The University of Melbourne The University of Melbourne Melbourne , VIC , Australia Parkville , VIC , Australia ISSN 0065-2598 ISSN 2214-8019 (electronic) Advances in Experimental Medicine and Biology ISBN 978-94-017-7415-4 ISBN 978-94-017-7417-8 (eBook) DOI 10.1007/978-94-017-7417-8 Library of Congress Control Number: 2015957431 Springer Dordrecht Heidelberg New York London © Springer Science+Business Media Dordrecht 2016 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfi lms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specifi c statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. Printed on acid-free paper Springer Science+Business Media B.V. Dordrecht is part of Springer Science+Business Media (www.springer.com) Pref ace Non-coding RNAs and the Reproductive System Reproduction is a fundamental feature of all known life and can be classifi ed into asexual and sexual reproduction. For successful sexual reproduction, both the internal and external organs have to develop and function properly to work together for procreation. Faults during development or maintenance of the reproductive system result in diseases that ultimately lead to infertility. In contrast to most other organ systems, it displays clear anatomical, morpho- logical and molecular differences between the two sexes, male and female. These include the testes, epididymis and prostate in males and ovary, uterus and mammary glands in females, as well as the sexual dimorphism of the secondary sexual characteristics such as external genitalia. The development of these organs is tightly regulated by a network of gene expression and func- tion in each of these organs as well as crosstalk between the organs through the production, secretion and reactivity to hormones. Until recently, the focus of reproductive science was the identifi cation of protein-coding genes that play important roles in the development of the dif- ferent organs and are mutated in diseases affecting the reproductive system, such as disorders of sex development, endometriosis, male and female infer- tility, as well as testicular, ovarian, prostate and breast cancer. However, in the last decade, it became obvious that focusing on protein-coding genes will only provide one part of the picture, as the regulatory role of non-coding RNAs became more and more apparent. These RNAs, which have little to no protein-coding potential, have been shown to regulate most if not all physio- logical processes, including the development and function of the reproductive organs, through transcriptional, post-transcriptional and epigenetic regulation of gene expression. Non-coding RNAs can be divided into different classes based on their size, their biogenesis and their protein partners. The main categories include microRNAs (miRNAs), small interfering RNAs (siRNAs), PIWI-interacting RNAs (piRNAs) and long non-coding RNAs (lncRNAs). While these molec- ular regulators have been studied extensively in the last few years, there are still many open questions with respect to their functions in driving biological processes. However, the rapid development of new technologies such as high- throughput sequencing to detect non-coding RNA expression and genome- editing tools such as the TALENs and CRISPR/CAS9 systems to analyse v vi Preface their in vivo function has accelerated the speed of new discoveries in a way not seen before. In this book, experts in reproductive biology discuss the fi nd- ings and advances we have made to elucidate the role of these new regulators of gene expression in the development of the reproductive organs and their contribution to disease. While the main focus is on the mammalian system, other model organisms that have been proven useful in the study of non- coding RNAs, such Drosophila and C. elegans , are also considered. The editors like to express their gratitude to all authors who have contrib- uted a review in their respective fi elds and to Springer Publisher, especially Sara Germans and Thijs van Vlijmen, who have worked closely with us to make this book happen. Parkville, VIC, Australia Dagmar Wilhelm Melbourne, VIC, Australia Pascal Bernard Contents 1 The Reproductive System .............................................................. 1 Andrew Pask 2 Non-coding RNAs: An Introduction ............................................. 13 Jennifer X. Yang , Raphael H. Rastetter , and Dagmar Wilhelm 3 How Many Non-coding RNAs Does It Take to Compensate Male/Female Genetic Imbalance? ................................................. 33 Jean-François Ouimette and Claire Rougeulle 4 The piRNA Pathway Guards the Germline Genome Against Transposable Elements .................................................................. 51 Katalin Fejes Tóth , Dubravka Pezic , Evelyn Stuwe , and Alexandre Webster 5 Non-coding RNA in Ovarian Development and Disease ............. 79 J. Browning Fitzgerald , Jitu George , and Lane K. Christenson 6 Non-coding RNA in Spermatogenesis and Epididymal Maturation .......................................................... 95 J. E. Holt , S. J. Stanger , B. Nixon , and E. A. McLaughlin 7 Non-coding RNAs in Mammary Gland Development and Disease ...................................................................................... 121 Gurveen K. Sandhu , Michael J.G. Milevskiy , Wesley Wilson , Annette M. Shewan , and Melissa A. Brown 8 Non-coding RNAs in Prostate Cancer: From Discovery to Clinical Applications .................................................................. 155 Yvonne Ceder 9 Non-coding RNAs in Uterine Development, Function and Disease ..................................................................... 171 Warren B. Nothnick Index ...................................................................................................... 191 vii The Reproductive System 1 Andrew Pask Abstract Correct sexual development is arguably the most important trait in an organism’s life history since it is directly related to its genetic fi tness. The developing gonad houses the germ cells, the only legacy we pass on to subsequent generations. Given the pivotal importance of correct reproduc- tive function, it is confounding that disorders of sex development (DSDs) are among the most common congenital abnormalities in humans (Lee et al. J Pediatr Urol 8(6):611–615, 2012 ). Urogenital development is a highly complex process involving coordinated interactions between molecular and hormonal pathways in a tightly regulated order. The con- trols that regulate some of the key events in this process are beginning to be unraveled. This chapter provides an overview of our understanding of urogenital development from the gonads to the urogenital ducts and exter- nal genitalia. Keywords Urogenital system • Testis • Ovary • External genitalia • Mammary gland • Sexual differentiation 1.1 Development of the Indifferent Gonadal Ridge The gonadal ridge fi rst appears as a bulge of inter- mediate mesoderm on the ventromedial surface of A. Pask (*) the intermediate embryonic kidney, the meso- School of BioSciences , The University of Melbourne , Melbourne , VIC 3010 , Australia nephros, at around 10.5 days post coitum (dpc) in e-mail: [email protected] mouse. At this stage, the gonad is identical in © Springer Science+Business Media Dordrecht 2016 1 D. Wilhelm, P. Bernard (eds.), Non-coding RNA and the Reproductive System, Advances in Experimental Medicine and Biology 886, DOI 10.1007/978-94-017-7417-8_1 2 A. Pask structure between males and females and is com- ates, and both organs increase in size. The prised largely of somatic cells with germ cells mesonephros contains the mesonephric and migrating in from surrounding tissues. The paramesonephric ducts that facilitate fl uid move- somatic cells will contribute to the supporting, ment during kidney development but will later interstitial and steroid-producing cell lineages, form aspects