Table Of ContentAdvances 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 h ttp://www.springer.com/series/5584
Dagmar Wilhelm (cid:129) P ascal B ernard
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
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Pref ace
Non-coding RNAs and the Reproductive System
R eproduction 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.
U ntil 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 D rosophila and C. elegans , are also considered.
T he 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
1
The Reproductive System
Andrew Pask
Abstract
C orrect 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, 2 012 ). 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 (cid:129) Testis (cid:129) Ovary (cid:129) External genitalia (cid:129) Mammary gland
(cid:129) 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 ,
nephros, at around 10.5 days post coitum (dpc) in
Melbourne , VIC 3010 , Australia
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 m esonephros contains the mesonephric and
migrating in from surrounding tissues. The paramesonephric ducts that facilitate fl uid move-
s omatic cells will contribute to the supporting, ment during kidney development but will later
interstitial and steroid-producing cell lineages, form aspects of the male and female reproductive
while the germ cells will form the gametes tracts respectively. Both ducts exist as paired
(Merchant-Larios et al. 1 993 ). As development structures that sit adjacent to the gonads (Fig. 1.1 ).
proceeds, the epithelium and underlying mesen- Several h omeobox genes including L hx1 , Lhx9
chyme of the gonad and mesonephros prolifer- and Emx2 have been implicated in the early pat-
Gonad
Mesonephros
Wolffian /
Mesonephric Duct
Müllerian /
Paramesonephric Duct
Urogenital Sinus
- SRY +SRY
- Testosterone + Testosterone
- AMH + AMH
Testis
Ovary
Epididymis
Oviduct
Vas Deferens
Bladder
Uterus
Bladder Seminal Vessicle
Vagina Prostate
Bulbourethral Gland
Penile Urethra
Fig. 1.1 S exual differentiation of the urogenital system. lower region of the vagina (b lack ) is derived from the uro-
The early embryo has a bipotential urogenital system (t op genital sinus. Male urogenital development occurs in the
diagram) that can proceed towards a female (l eft) or male presence of a testis and the subsequent production of AMH
(r ight) fate. Female urogenital development occurs in the and testosterone. AMH actively drives the regression of the
absence of testis development and subsequent absence of paramesonephric ducts while testosterone promotes the dif-
AMH and testosterone. Under these conditions the ferentiation of the Wolffi an ducts to form the epididymis,
Wolffi an/mesonephric duct will fail to proliferate while the vas deferens, seminal vesicle, prostate and bulbourethral
Müllerian/paramesonephric duct will develop in to the ovi- glands ( blue ). The penile urethra forms from the fusion of
duct, uterus and upper portion of the vagina (p ink ). The tissue from the urogenital sinus and urorectal septum
