BIOLOGY OF REPRODUCTION (2016) 95(1):10, 1–8
Published online before print 27 April 2016.
DOI 10.1095/biolreprod.116.138768

Minireview

Is the Epididymis a Series of Organs Placed Side By Side?1

Raquel F. Domeniconi,3 Ana Cláudia Ferreira Souza,4 Bingfang Xu, Angela M. Washington, and Barry T.
Hinton2

Department of Cell Biology, University of Virginia Health System, Charlottesville, Virginia

ABSTRACT

The mammalian epididymis is more than a highly convoluted
tube divided into four regions: initial segment, caput, corpus and
cauda. It is a highly segmented structure with each segment
expressing its own and overlapping genes, proteins, and signal
transduction pathways. Therefore, the epididymis may be
viewed as a series of organs placed side by side. In this review
we discuss the contributions of septa that divide the epididymis
into segments and present hypotheses as to the mechanism by
which septa form. The mechanisms of Wolffian duct segmenta-
tion are likened to the mechanisms of segmentation of the renal
nephron and somites. The renal nephron may provide valuable
clues as to how the Wolffian duct is patterned during
development, whereas somitogenesis may provide clues as to
the timing of the development of each segment. Emphasis is also
placed upon how segments are differentially regulated, in
support of the idea that the epididymis can be considered a
series of multiple organs placed side by side. One region in
particular, the initial segment, which consists of 2 or 4 segments
in mice and rats, respectively, is unique with respect to its
regulation and vascularity compared to other segments; loss of
development of these segments leads to male infertility.
Different ways of thinking about how the epididymis functions
may provide new directions and ideas as to how sperm
maturation takes place.

epididymal segments, epididymis, gene expression, male fertility,
Wolffian duct

INTRODUCTION

It is often written that the epididymis is a highly convoluted
tube divided into four regions: initial segment, caput, corpus,
and cauda. It is only over the past several years that the initial
segment has been included in this list, showing that this region
is now viewed separately from the caput region. Furthermore, it
has been established that, at least for rodents, the epididymis is
subdivided into segments separated by septa [1]. In view of the
repertoire of genes that are expressed in each segment, we can
consider the epididymis a series of small organs placed side by
side. How these segments coordinate with each other to ensure
that spermatozoa come into contact with the proper luminal
microenvironment is not known. This microenvironment is
critical for sperm maturation. To add another level of
complexity, each segment appears to have unique and common
regulators of gene and protein expression and signaling events.
Putting this all together, it is obvious that the description of the
epididymis as a highly convoluted tubule is much simplified.
Much of this review focuses on the rodent epididymis, but
where possible, we have referenced what is known in other
species.

CONTRIBUTION OF SEPTA TO SEGMENTATION

For clarity, the classical divisions of the epididymis, the
initial segment, caput, corpus and cauda, will be referred to as
regions whereas segments are defined as the points where the
convoluted duct is separated by a septum. For comparison,
Figure 1 illustrates two rat epididymides, one illustrates regions
and the other illustrates segments. Segmentation of the duct
begins as early as Embryonic Day 18 (E18) and is obvious
during early postnatal stages, and segmentation progresses
from anterior to posterior (also referred to as proximal to distal
in some publications) in line with ductal coiling [2]. It is
possible that septa originate from the walls of the capsule
surrounding the duct, similar to septa formation in the heart.
However, it is not clear what determines the position of each
septum during development. Septa could be predetermined at
precise points during development (regardless of the length of
duct and its degree of coiling) and/or initiate at a certain time
when ductal elongation and coiling are optimal at that
particular point. Further studies of the formation of septa will
be greatly improved by identification of a specific marker,
although presumably, septa contain collagen [3], elastic fibers,
interstitial cells and blood vessels. Whichever mechanism(s) is
responsible for their formation, the epididymis is always
divided into the number of segments that is dependent upon the
species, except for humans (see below).

For the adult mouse 10 segments were identified and 19 for
the adult rat [4–7]. However, based upon differential gene

1Supported by Fundação de Amparo à Pesquisa do Estado de São Paulo
grant 2014/23382-9 to R.F.D., Coordenação de Aperfeiçoamento de
Pessoal de Nı́vel Superior grant BEX 5874/14-9 to A.C.F.S., and Eunice
Kennedy Shriver National Institute of Child Health and Human
Development/National Institutes of Health grant R01 HD068365 and
RO1 HD069654 to B.T.H.
2Correspondence: Barry T. Hinton, Department of Cell Biology,
University of Virginia Health System, PO Box 800732, Charlottesville,
VA 22908. E-mail: bth7c@virginia.edu
3Current address: Department of Anatomy, Institute of Biosciences,
University Estadual Paulista, Botucatu, SP, Brazil.
4Current address: Department of General Biology, Federal University of
Viçosa, Viçosa, Minas Gerais, Brazil.

Received: 14 January 2016.
First decision: 3 February 2016.
Accepted: 15 April 2016.
� 2016 by the Society for the Study of Reproduction, Inc. This article is
available under a Creative Commons License 4.0 (Attribution-Non-
Commercial), as described at http://creativecommons.org/licenses/by-nc/
4.0
eISSN: 1529-7268 http://www.biolreprod.org
ISSN: 0006-3363

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expression, Zhang et al. [8] split rat epididymis segment
number 12 (corpus region) into 12A and 12B (Figs. 1 and 2,
respectively). In addition to separating the duct into distinct
segments, the function and anatomical three-dimensional
arrangement of septa are not known. What is the relationship
between the septum and the point at which the duct passes
through that septum? How tightly does the septum surround the
duct at that point? Presumably, septa aid in supporting
individual segments but also carry blood vessels and nerves
deep into the tissue. Studies by Turner et al. [9] suggested septa
limit paracrine signals within individual segments and that such
signals do not cross the septal boundary from one segment to
another. This is an intriguing hypothesis especially in light of
the expression of genes, proteins, and signaling pathways in
each segment. However, interstitial fluid flow, which presum-
ably can move across or through septal boundaries, may play a
role in generating gradients of paracrine molecules across
segments. When the interstitium of segments in the cauda
region were inoculated with bacteria, the infection stayed
within that segment; the septa acted as diffusion barriers [10].
The human epididymis is more complex, and, although several
reports have shown 5–10 regions [11–13], the exact number of
segments is unclear. It does appear that the septa do not
completely traverse the entire duct, are not as well organized as
observed in the rat and mouse, and are differently placed from
one human epididymis to another (R. Sullivan, personal
communication). Although investigators have used regions to
describe the different parts of the epididymis of other species,
including boar [14, 15], ram [16, 17], echidna [18],
cynomolgus monkey [19], and horse [16], upon closer
inspection of the images presented by the authors of the above
studies, it is apparent that distinct segments are present.

CAN AN UNDERSTANDING OF SEGMENTATION OF
OTHER TISSUES HELP UNDERSTAND THE SEGMENTA-
TION OF THE WOLFFIAN DUCT?

It may be helpful to understand the mechanisms of Wolffian
duct segmentation by examining what is known about the
mechanisms of segmentation of other developing structures.
Somite and renal nephron segmentation are excellent examples
of the development of segmented organs [20–24]. Segmenta-
tion of the renal nephron/tubule is particularly relevant given

FIG. 1. Comparison of epididymal regions with epididymal segments in
the rat. Segments 1–4 correspond to the initial segment, intermediate zone
(IZ) segments 5–11 correspond to the caput region, segments 12–13 and
14 correspond to the corpus region, and segments 14 and 15–19
correspond to the cauda region (diagram adapted from Robaire et al.
[113]; epididymal segments illustration courtesy of Prof. YL Zhang,
Institute of Biochemistry and Cell Biology, Shanghai Institutes for
Biological Sciences, Shanghai, China).

FIG. 2. Expression of defensin mRNA in different epididymal segments of the rat (figure was modified from Zhang et al. [8], with permission; data from
Jelinsky et al. [5]). The 6 epididymides to the left show sequential expression, and the 2 on the right show one example of 1 defensin mRNA expressed in
multiple segments in a row (Defb30), and the other shows a mosaic pattern of expression (Defb33). The color-coded bar below show degree of expression,
with red having the highest expression. (Epididymis figures courtesy of Prof. YL Zhang [Institute of Biochemistry and Cell Biology, Shanghai Institutes for
Biological Sciences, Shanghai, China] with permission of American Society of Andrology.)

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that both the kidney and the epididymis are derived from the
same ductal system and have similar physiological functions,
for example, transport of ions and organic solutes. Much of the
work on segmentation of the renal nephron has been performed
using several animal models including fish (e.g., zebrafish),
amphibians (e.g., Xenopus spp), birds (e.g., chicks), and mice.
Similar to the Wolffian duct, there are several regions along the
renal tubule where each region is divided into segments:
convoluted proximal tubule (segments PS1 and PS2), straight
tubule (segment S3), loop of Henle (descending thin limb and
ascending thin limb segments) and distal tubule (thick
ascending limb and distal convoluted tubule/loop segments).
The distal convoluted tubule is connected to the collecting duct
system that consists of two segments, the collecting tubule and
the connecting duct.

The mechanisms by which the renal nephron undergoes
proximal–distal patterning are not known, but there is evidence
to suggest that several genes, including the transcription factors
Irx5 and Irx36 [25, 26], Notch [27–29], and Caudal [30] are
necessary for proximal and distal tubule formation. WNT
signaling has been implicated in the formation of the mouse
renal nephron; for example, loss of Wnt9b results in the failure
of nephron formation and also formation of the Wolffian duct
[31]. Using chick mesonephros, Schneider et al. [32]
demonstrated the importance of WNT signaling in patterning
the proximal–distal nephron axis. If an ectopic WNT ligand
was expressed at right angles to the axis of the endogenous
WNT signal (within the coelomic epithelium), then the
nephron axis was reoriented. Certainly, components of the
WNT signaling pathway are expressed in the adult epididymis
[33–36], but whether WNT signaling plays a role in proximal–
distal patterning of the Wolffian duct remains to be examined.

In addition to the mechanisms involved in proximal–distal
patterning, the mechanisms of timing of segment formation
along the Wolffian are also unknown. In this instance,
examining the processes of timing during somitogenesis may
be of help. The total number of somites formed is constant and
species-specific, which is a characteristic similar to that in the
formation of epididymal segments. The time of formation for
each somite along the body axis from anterior to posterior has
been determined for several species. It turns out that this timing
is due to a cellular oscillator/segmentation clock (a clock and
wavefront model) [37]. For example, expression of the chick
hairy and enhancer of split 4 (HES4) gene was shown to cycle
90 min in the presomatic mesoderm, the time needed to
generate a somite [37–39]. In addition, lunatic fringe (Ifng)
[40] and other NOTCH pathway-related genes such as the
transcription family hairy and enhancer of split (Hes, Hes-
related, and Her family) and the WNT signaling pathway were
shown to play critical roles in the generation of oscillations (see
reviews in references [20, 21, 41]). FGF8 forms a gradient
(retinoic acid forms an opposing gradient) [42, 43] that, in turn,
will generate a graded FGF signaling event in each putative
somite; the point where a group of cells respond to FGFs would
be the wavefront. This signaling event results in the
arrangement of segmental boundaries [39].

As posed at the beginning of this section, could an
understanding of segmentation of another segmented structure
help understand segmentation of the Wolffian duct? In
comparison with somitogenesis, it is clear that 1) the number
of segments of the Wolffian duct is constant and specific for
each species; 2) many genes involved in the segmentation of
somites are also expressed in the developing Wolffian duct
[44]; 3) FGFs are expressed within each segment, although that
is only shown for the adult epididymis [45]; and 4)
segmentation is observed from anterior to posterior. A major

difference is that the individual segments (somites) are formed
and positioned in sequence, whereas the Wolffian duct is
already formed, and segmentation involves elongation, coiling,
and generation of a septum (segment boundary). Also, each
epididymal segment is not uniform but is of different shapes,
sizes, and positions [46]. However, it is still tempting to
hypothesize that segmentation involves an oscillator/clock that
results in the sequential generation of a segment. In further
support of this hypothesis, a gradient of inhibin beta A (Inhba)
has been shown to exist along the anterior–posterior axis of the
Wolffian duct, with the highest expression observed at the most
anterior mesenchymal cell compartment [47, 48]. Loss of
Inhba resulted in loss of coiling and subsequent loss of
segmentation [48]. There is some evidence to suggest that
collective cell movements may synchronize locally coupled
oscillators, which in turn promote global synchronization for
the generation of segmented structures [49]. This is of special
interest in light of recent findings that one of the major driving
forces of elongation and coiling of the Wolffian duct is cell
rearrangement [50]. Loss of Pkd1, a gene involved in
autosomal dominant polycystic kidney disease, also results in
loss of coiling of the Wolffian duct during development,
thereby suggesting that the TGF-b/BMP signaling pathway
may also regulate coiling and possibly segment formation [51].

Homeobox (Hox) genes also play a role in segmentation of
structures, and there is evidence from a microarray screen that
the developing Wolffian duct expresses several Hox genes
(Hoxc9, Hoxd10, Hoxa11, Hoxc4, Hoxc10, Hoxd4, Hoxd8, and
Hoxd13), and other homeobox-containing genes such as meis
homeobox 2 (Meis2), cut-like homeobox 2 (Cux2), Lim
homeobox protein 1 (Lhx1) gene, and Mohawk homeobox
(Mkx) [44]. Other investigators have identified similar and
additional Hox and homeobox-containing genes in the
developing Wolffian duct, including Hoxa10, Hoxa13 [52–
56], paired box 2 (Pax2), Pax8, Meis1, lens intrinsic membrane
protein 2 (Lim2), T-cell leukemia, homeobox 2 (Tlx2), and
ladybird homeobox homolog 2 (Lbx2) [57, 58]. It is not known
whether one or more Hox genes are responsible for
segmentation, but it is clear that during embryonic develop-
ment of the Wolffian duct, 1) Hoxc4 is expressed in the efferent
ducts and the entire Wolffian duct, but not the vas deferens; 2)
Hoxc9 is expressed along the entire Wolffian duct but not the
efferent ducts and vas deferens; and 3) Hoxa11, Hoxd10, and
Hoxd13 are expressed only in the vas deferens during
embryonic development. These data suggest that, from a
regional perspective, Hoxc4 and Hoxc9 may play a role in
boundary formation between the efferent ducts and epididymis.
Interestingly, Lfng may be involved in boundary formation
between the efferent ducts and testis or at least involved in the
connection between the efferent ducts and testis [59]. Loss of
Hoxa11 and Hoxa10 results in homeotic transformation of the
vas deferens into cauda, which is also indicative of this gene
playing a role in boundary formation between the cauda and
vas deferens [55, 60]. Another group of homeobox-containing
genes, reproductive hox (Rhox) [61], are expressed in the
epididymis, but whether any members of this family are
involved in the development of segmentation remains to be
determined. Rhox5 may be involved in the development of the
initial segment and caput region in mice and the cauda region
in rats [62].

EPIDIDYMAL SEGMENTS EXPRESS UNIQUE AND
OVERLAPPING GENES

Although it has been well established that each epididymal
region of several species expresses its own repertoire and those

THE EPIDIDYMIS IS A SERIES OF JOINED ORGANS

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of overlapping genes and proteins, it was the studies by
Johnston et al. [5] and Jelinski et al. [63] that showed discrete
segments express their own gene and overlapping repertoire.
Figure 2 shows an example of such expression. More recently,
investigators have used segment terminology in identification
of proteins by using immunolocalization approaches, for
example, neutral endopeptidase analysis [3]. Those findings
have allowed those working on the epididymis to be more
precise in defining the expression of genes and proteins and,
hopefully, functions at those discrete segments. The authors
encourage those working on the epididymis to use segment
nomenclature. It will also allow investigators to generate
segment-specific conditional knockout mice and so identify
those segments that are critical for sperm maturation. A number
of region-specific expression studies using Cre-recombinases
have been used to conditionally remove genes from that region,
for example, ribonuclease, RNase A family, 10 (Rnase10),
which is active in the initial segment with some proximal caput
overlap [64]; lipocalin 5 (Lcn5; active in the caput) [65]; and
defensin beta 41 (Defb41; active in the initial segment) [66];
but not single-segment–specific expression of Cre-recombi-
nases.

It has been technically difficult to identify the expression of
genes along different regions of the epididymal duct during
embryonic development, although studies have revealed
differences in gene expression as early as E12.5 between the
mesonephric tubules (which will form the efferent ducts, the
entire Wolffian/mesonephric duct, and the vas deferens;
GenitoUrinary Development Molecular Anatomy Project
[GUDMAP]; http://www.gudmap.org/index.html) [44]. For
example, the GUDMAP database shows in situ hybridization
localization of the collagen triple helix repeat containing 1
(Cthrc1) gene in both mouse mesonephric tubules and
Wolffian/mesonephric ducts at E10.5. However, at E12.5,
Cthrc1 was only localized to mesonephric tubules. The
proprotein convertase subtilisin/kexin type 9 (Pcsk9) gene
was localized to the mesonephric tubules at both E10.5 and
E12.5. It would also be of great interest to identify gradients of
gene expression along the entire duct. More studies are
required to identify specific gene expression and putative
signaling pathways during and following the development of a
segment. The findings will also help in identification of
putative segmentation clock genes as described above.

More recently, investigators have performed micro-RNA
(miRNA) and Piwi-interacting RNA (piRNA) profiling along
adult mouse, rat, and human epididymal ducts [8, 67–69], but
because the profiling was performed in regions and not
segments, it is not clear if miRNAs play a role in the
development of segments and/or their function in the adult.

LACK OF INITIAL SEGMENT RESULTS IN MALE INFER-
TILITY

In the mouse, there are 2 segments associated with the initial
segment. The rat has 4, and the human is more complex.
Human epididymis has a discontinuous initial segment-like
epithelium (epithelium VII), and the initial segment does not
form a gross anatomical appearance similar to that seen in other
species [70]. The earliest indication that the initial segment was
important for male fertility came from a study using mice that
had a null mutation in the Ros1 proto-oncogene (Ros1), an
orphan tyrosine kinase receptor [71]. Both the extracellular
domain and the kinase domain were found to play a role in the
male infertility phenotype. Follow-up studies revealed an
interesting sperm phenotype [72–75], in which the sperm were
unable to volume regulate once in the female reproductive tract

and displayed hairpin bends at the mid-piece, resulting in
failure to fertilize an egg. The function of Ros1 playing a role
in the initial segment has been confirmed [76]. A very similar
phenotype was observed in which the large T antigen was
targeted to the initial segment/caput regions by using the
glutathione peroxidase 5 (Gpx5) promoter, although the
mechanism by which the hairpin bends formed differed from
that in the Ros1 knockout animal [77, 78]. In addition, a similar
sperm phenotype was observed in mice in which the
phosphatase and tensin homolog (Pten) gene was conditionally
removed from the initial segment. In that instance, hairpin
bends were observed in spermatozoa as they progressed along
the epididymal duct. In addition to all three animal mutations
having similar sperm phenotypes, it was suggested that a
common underlying mechanism of loss of function of the
initial segment was a defect in cellular differentiation [79]. In
the case of the Ros1 null mutation, the initial segment failed to
undergo differentiation during the prepubertal period, whereas
in the conditional Pten knockout mice, the initial segment
underwent dedifferentiation [79]. It remains to be seen whether
any initial segment genes that regulate male fertility are
potential targets for the development of a human male
contraceptive. Ros1 is expressed in human epididymis but is
not confined to the proximal region [80].

Another unique feature of the initial segment region is its
intense vascularity, which is very obvious in the epididymis of
several species [46, 81, 82] and is reflected in its blood flow
compared to the remainder of the epididymis [83]. Suzuki [84]
defined two types of anatomical arrangements of capillaries
surrounding the seminiferous tubules and different regions
along the epididymis of the mouse: testicular type and
deferential type. Initial segment and cauda region capillaries
are differentially arranged, which is characterized by having
arterioles and venules running parallel to the duct for a
considerable length before (or after) communicating with the
capillary network. There is much interconnectivity between the
capillaries surrounding the initial segment duct. The vascular
arrangement surrounding the initial segment duct is absent in
Ros1 knockout and XX sex reversed (XXSxr) mice [85],
presumably due to the failure of the initial segment to develop.
Further studies showed that the loss of the initial segment in
XXSrx males was androgen-independent [85], maybe pointing
to the role of testicular factors. These studies also demonstrated
the intimate relationship between development of the initial
segment and concomitant development of its vasculature. In
addition, Gpx5-Tag2 mice, in which the SV40 tag is under the
control of the Gpx5 promoter [77], which is highly expressed in
the proximal region of the epididymis, show a developed initial
segment that lacks the degree of vasculature found in control
initial segments. This initial segment epithelium did show an
increase in apoptosis compared to that in control and was
dysplastic. Both of the phenotypes could certainly alter the
function of the initial segment, resulting in the failure of the
vasculature to develop. The capillaries within the mouse initial
segment, segment 1 only, are fenestrated [86], whereas the
more distal segments are nonfenestrated. The function of
fenestrated capillaries within segment 1 are not known,
although it is often speculated that fenestration allows for
rapid interchange of fluid and epididymal luminal fluid
components between the epididymis and blood. However,
more than 90% of testicular fluid is absorbed along the efferent
ducts [87, 88], so it is not clear as to the reason why the
capillaries in this region are fenestrated. Although there is a
network of capillaries within the initial segment, it has the
lowest percentage of lymphatic capillaries per epididymal
interstitium (0.69%) compared to the more distal regions; the

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cauda showing the most (4.92%) [89]. More studies are
required that examine the development of the initial segment
vasculature and the influence played by the initial segment
epithelium on its development (and/or vice versa).

INITIAL SEGMENT IS UNIQUELY REGULATED COM-
PARED TO OTHER REGIONS

A clue to the uniqueness of the regulation of this epididymal
region originated from early studies in which the efferent ducts
were ligated and cellular apoptosis was observed throughout
the initial segment epithelium [90–93]. Apoptosis could not be
reversed by exogenous administration of testosterone or
dihydrotestosterone. Further studies clarified the degree and
rate of apoptosis [94, 95]. These and other studies hypothesized
that luminal fluid components or lumicrine factors were
responsible for cell survival in the initial segment, and
lumicrine regulation was a unique regulation feature of the
initial segment [96]. Examining the roles of lumicrine factors in
the course of development of the initial segment revealed that
lumicrine factors regulated initial segment differentiation [9,
97]. During the differentiation stage, lumicrine factors were
required for both cell proliferation and cell survival of
differentiating epithelial cells in the initial segment. During
the postdifferentiation stage, lumicrine factors were required
for cell survival of differentiated cells in the initial segment
epithelium [9, 97]. Among the multiple signal pathways, the
ERK pathway was in the center of lumicrine regulation [79, 98,
99], which rapidly responded to stimulation and loss of
lumicrine factors. A high activity level of the ERK pathway
was a feature of the differentiated initial segment that was
distinct compared to other regions [79, 98, 99]. Although the
identity of lumicrine factors was unknown, BMPs [100, 101],
fibroblast growth factors [102], and luminal fluid androgen
[58] have been suggested to be putative lumicrine factors. It
was hypothesized that growth factors regulated permissive
signal pathways, including the ERK pathway, while non-
genomic actions of androgen receptor (AR) enhanced signal
transduction regulation. Interestingly, earlier studies by Brooks
[103] clearly showed that lumicrine factors are also negative
regulators of protein synthesis and secretion by the initial
segment epithelium. Upon closer inspection of the initial
segment epithelium following efferent duct ligation, it was
clear that not all cells underwent apoptosis. Could there be two
distinct cell populations of cells within the initial segment?
Different lineages? Stem cell-like population?

It is possible that lumicrine factors are secreted by
epididymal regions, which in turn regulate the function of
downstream regions [104]. Ligation of the duct between the
distal caput and proximal corpus (corresponding to segments 6
and 7, respectively [5]) resulted in microscopic cellular
changes in the epithelium of the corpus (segment 7). However,
these data could also be interpreted as the result of the absence
of testicular luminal fluid factors. Further studies are needed to
test the hypothesis that lumicrine factors are secreted by the
epididymal epithelium, which in turn regulate the functions of
downstream epithelial cells.

ARE OTHER SEGMENTS DIFFERENTIALLY REGULATED?

Extensive genomic and proteomic studies have clearly
shown that testosterone and 5a-testosterone up- and down-
regulate the expression of genes and proteins along different
regions of the epididymis [58]. For example, c-glutamyl
transpeptidase (Ggt) mRNA IV is down-regulated in the rat
initial segment following orchiectomy, but the same mRNA is
up-regulated in the cauda region [105]. The fucosyltransferase

(Fut) family of genes is upregulated (Fut1 and Fut 4) and
downregulated (Fut2 and Fut9) in the caput region following
loss of androgens [106]. There are many more examples
showing differential regulation of expression of genes and
proteins at the regional level. Presumably, the cells in each
region (segment?) express a unique repertoire of transcription
factors that respond to androgens by enhancing or repressing
gene expression.

LUMINAL FLUID COMPOSITION CHANGES ALONG
THE EPIDIDYMAL DUCT SEGMENT BY SEGMENT

If we consider each segment as an individual ‘‘organ,’’ then
presumably the luminal fluid milieu changes segment by
segment. Each segment will contribute in unique ways to that
luminal fluid microenvironment via secretion, absorption,
sperm modifications contributing to changes of that fluid at
that segment and epididymosome secretion. Examination of the
composition of the luminal fluid at each region clearly shows it
rapidly changes from one region to the next (see reviews in [58,
107]). An example of changes of luminal fluid composition
from one segment to the next is the sudden appearance of L-
carnitine in the fluid of the rat distal caput region (region 2a)
[108]; it was not present in the luminal fluid of the proximal
caput region (region 2) [108]. Comparing the numbered
epididymal micropuncture sites with the numbering of each
segment in the rat epididymis [4], region 2 corresponds to
segment 3, and region 2a corresponds to segment 4, the same
location in which the specific L-carnitine transporter OCTN2
was identified [109]. Micropuncture studies can be used to
collect fluid from different regions, but it will be technically
challenging to collect fluid from only one discrete segment for
analysis. However, an approach, the split-drop stopped-flow
micropuncture technique, was used to measure the secretion of
amino acids at discrete segments [110].

It is the combination of cell types within that region/
segment that is responsible for generating a unique luminal
fluid milieu within that segment. We are beginning to
understand the functions of each cell type. However, cells do
not function in isolation but interact with neighboring and/or
downstream cells via paracrine mechanisms. Therefore, it is
important to uncover those mechanisms by which the different
cell types, within the same region/segment, communicate or
cross-talk with each other. This is well illustrated in the studies
by Breton et al. [111] and Shum et al. [112], in which
communication between clear, principal, and basal cells is
essential in generating an optimal luminal fluid pH and
bicarbonate concentration for sperm maturation.

A UNITED ORGAN

‘‘The real voyage of discovery does not consist in seeing
new landscapes but having new eyes.’’— Marcel Proust

It is time to think in a different light about how the
epididymis functions, if we are to uncover new and unique
processes that are critical to sperm maturation. Thinking about
the epididymis as a series of organs side-by-side is one way,
but other ways of thinking will contribute. For example,
examining the development of the Wolffian duct can be
thought of in terms of the development of a biological tube.
How do tubes form? How do tubes coil? How do tubes
segment? Let us see how other organs tackle this issue and then
see if we observe similar or dissimilar morphogenic events or
mechanisms between other biological tubes and the Wolffian/
epididymal duct. Examining the functions of other segmented
structures, for example, the formation of the renal nephron and

THE EPIDIDYMIS IS A SERIES OF JOINED ORGANS

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somites presented in this review may provide clues as to how
epididymal segmentation is regulated. Although this may be
considered blasphemy, we could think about the epididymis as
an organ first, forgetting about sperm maturation. One mentor
to one of the authors (BTH) once said: ‘‘The testis would be a
wonderful organ to study if it were not for those darn sperm.’’
Perhaps ‘‘the epididymis would be a wonderful organ to study
if it were not for those darn sperm.’’ It is just another way of
thinking and the paths that open up with this way of thinking
may well uncover how sperm maturation takes place.

REFERENCES

1. Turner TT, Bomgardner D, Jacobs JP, Nguyen QA. Association of
segmentation of the epididymal interstitium with segmented tubule
function in rats and mice. Reproduction 2003; 125:871–878.

2. Hinton BT, Galdamez MM, Sutherland A, Bomgardner D, Xu B, Abdel-
Fattah R, Yang L. How do you get six meters of epididymis inside a
human scrotum? J Androl 2011; 32:558–564.

3. Thong A, Muller D, Feuerstacke C, Mietens A, Stammler A,
Middendorff R. Neutral endopeptidase (CD10) is abundantly expressed
in the epididymis and localized to a distinct population of epithelial
cells–its relevance for CNP degradation. Mol Cell Endocrinol 2014; 382:
234–243.

4. Johnston DS, Turner TT, Finger JN, Owtscharuk TL, Kopf GS, Jelinsky
SA. Identification of epididymis-specific transcripts in the mouse and rat
by transcriptional profiling. Asian J Androl 2007; 9:522–527.

5. Jelinsky SA, Turner TT, Bang HJ, Finger JN, Solarz MK, Wilson E,
Brown EL, Kopf GS, Johnston DS. The rat epididymal transcriptome:
comparison of segmental gene expression in the rat and mouse
epididymides. Biol Reprod 2007; 76:561–570.

6. Adamali HI, Somani IH, Huang JQ, Mahuran D, Gravel RA, Trasler JM,
Hermo LI. Abnormalities in cells of the testis, efferent ducts, and
epididymis in juvenile and adult mice with beta-hexosaminidase A and B
deficiency. J Androl 1999; 20:779–802.

7. Adamali HI, Somani IH, Huang JQ, Gravel RA, Trasler JM, Hermo L II.
Characterization and development of the regional- and cellular-specific
abnormalities in the epididymis of mice with beta-hexosaminidase A
deficiency. J Androl 1999; 20:803–824.

8. Zhang YL, Zhang JS, Zhou YC, Zhao Y, Ni MJ. Identification of
microRNAs and application of RNA interference for gene targeting in
vivo in the rat epididymis. J Androl 2011; 32:587–591.

9. Turner TT, Johnston DS, Jelinsky SA, Tomsig JL, Finger JN. Segment
boundaries of the adult rat epididymis limit interstitial signaling by
potential paracrine factors and segments lose differential gene expression
after efferent duct ligation. Asian J Androl 2007; 9:565–573.

10. Stammler A, Hau T, Bhushan S, Meinhardt A, Jonigk D, Lippmann T,
Pilatz A, Schneider-Huther I, Middendorff R. Epididymitis: ascending
infection restricted by segmental boundaries. Hum Reprod 2015; 30:
1557–1565.

11. Holstein AF. Morphologische Studien am Nebenhoden des Menschen.
In: Bargman W. Doerr W (eds) Zwanglose Abhandlungen aus dem
Gebiet der normalen und pathologischen Anatomie. Stuttgart: Georg
Thieme Verlag; 1969; 1–99.

12. Soler C, Perez-Sanchez F, Schulze H, Bergmann M, Oberpenning F,
Yeung C, Cooper TG. Objective evaluation of the morphology of human
epididymal sperm heads. Int J Androl 2000; 23:77–84.

13. Yeung CH, Cooper TG, Oberpenning F, Schulze H, Nieschlag E.
Changes in movement characteristics of human spermatozoa along the
length of the epididymis. Biol Reprod 1993; 49:274–280.

14. Dacheux JL, Castella S, Gatti JL, Dacheux F. Epididymal cell secretory
activities and the role of proteins in boar sperm maturation. Therioge-
nology 2005; 63:319–341.

15. Guyonnet B, Marot G, Dacheux JL, Mercat MJ, Schwob S, Jaffrezic F,
Gatti JL. The adult boar testicular and epididymal transcriptomes. BMC
Genomics 2009; 10:369.

16. Fouchecourt S, Dacheux F, Dacheux JL. Glutathione-independent
prostaglandin D2 synthase in ram and stallion epididymal fluids: origin
and regulation. Biol Reprod 1999; 60:558–566.

17. Gatti JL, Castella S, Dacheux F, Ecroyd H, Metayer S, Thimon V,
Dacheux JL. Post-testicular sperm environment and fertility. Anim
Reprod Sci 2004; 82-83:321–339.

18. Grutzner F, Nixon B, Jones RC. Reproductive biology in egg-laying
mammals. Sex Dev 2008; 2:115–127.

19. Yeung CH, Weinbauer GF, Cooper TG. Responses of monkey

epididymal sperm of different maturational status to second messengers
mediating protein tyrosine phosphorylation, acrosome reaction, and
motility. Mol Reprod Dev 1999; 54:194–202.

20. Pourquie O. The segmentation clock: converting embryonic time into
spatial pattern. Science 2003; 301:328–330.

21. Hubaud A, Pourquie O. Signalling dynamics in vertebrate segmentation.
Nat Rev Mol Cell Biol 2014; 15:709–721.

22. Resende TP, Andrade RP, Palmeirim I. Timing embryo segmentation:
dynamics and regulatory mechanisms of the vertebrate segmentation
clock. Biomed Res Int 2014; 2014:718683.

23. Webb AB, Oates AC. Timing by rhythms: daily clocks and develop-
mental rulers. Dev Growth Differ 2016; 58:43–58.

24. Yabe T, Takada S. Molecular mechanism for cyclic generation of
somites: Lessons from mice and zebrafish. Dev Growth Differ 2016; 58:
31–42.

25. Alarcon P, Rodriguez-Seguel E, Fernandez-Gonzalez A, Rubio R,
Gomez-Skarmeta JL. A dual requirement for Iroquois genes during
Xenopus kidney development. Development 2008; 135:3197–3207.

26. Reggiani L, Raciti D, Airik R, Kispert A, Brandli AW. The prepattern
transcription factor Irx3 directs nephron segment identity. Genes Dev
2007; 21:2358–2370.

27. Cheng HT, Kim M, Valerius MT, Surendran K, Schuster-Gossler K,
Gossler A, McMahon AP, Kopan R. Notch2, but not Notch1, is required
for proximal fate acquisition in the mammalian nephron. Development
2007; 134:801–811.

28. Cheng HT, Kopan R. The role of Notch signaling in specification of
podocyte and proximal tubules within the developing mouse kidney.
Kidney Int 2005; 68:1951–1952.

29. Cheng HT, Miner JH, Lin M, Tansey MG, Roth K, Kopan R. Gamma-
secretase activity is dispensable for mesenchyme-to-epithelium transition
but required for podocyte and proximal tubule formation in developing
mouse kidney. Development 2003; 130:5031–5042.

30. Wingert RA, Selleck R, Yu J, Song HD, Chen Z, Song A, Zhou Y,
Thisse B, Thisse C, McMahon AP, Davidson AJ. The cdx genes and
retinoic acid control the positioning and segmentation of the zebrafish
pronephros. PLoS Genet 2007; 3:1922–1938.

31. Carroll TJ, Park JS, Hayashi S, Majumdar A, McMahon AP. Wnt9b
plays a central role in the regulation of mesenchymal to epithelial
transitions underlying organogenesis of the mammalian urogenital
system. Dev Cell 2005; 9:283–292.

32. Schneider J, Arraf AA, Grinstein M, Yelin R, Schultheiss TM. Wnt
signaling orients the proximal–distal axis of chick kidney nephrons.
Development 2015; 142:2686–2695.

33. Wang K, Li N, Yeung CH, Cooper TG, Liu XX, Liu J, Wang WT, Li Y,
Shi H, Liu FJ. Comparison of gene expression of the oncogenic Wnt/
beta-catenin signaling pathway components in the mouse and human
epididymis. Asian J Androl 2015; 17:1006–1011.

34. Lombardi AP, Royer C, Pisolato R, Cavalcanti FN, Lucas TF, Lazari
MF, Porto CS. Physiopathological aspects of the Wnt/beta-catenin
signaling pathway in the male reproductive system. Spermatogenesis
2013; 3:e23181.

35. Deshpande SN, Vijayakumar G, Rao AJ. Oestrogenic regulation and
differential expression of WNT4 in the bonnet monkey and rodent
epididymis. Reprod Biomed Online 2009; 18:555–561.

36. DeBellefeuille S, Hermo L, Gregory M, Dufresne J, Cyr DG. Catenins in
the rat epididymis: their expression and regulation in adulthood and
during postnatal development. Endocrinology 2003; 144:5040–5049.

37. Cooke J, Zeeman EC. A clock and wavefront model for control of the
number of repeated structures during animal morphogenesis. J Theor Biol
1976; 58:455–476.

38. Palmeirim I, Henrique D, Ish-Horowicz D, Pourquie O. Avian hairy gene
expression identifies a molecular clock linked to vertebrate segmentation
and somitogenesis. Cell 1997; 91:639–648.

39. Dubrulle J, McGrew MJ, Pourquie O. FGF signaling controls somite
boundary position and regulates segmentation clock control of
spatiotemporal Hox gene activation. Cell 2001; 106:219–232.

40. Forsberg H, Crozet F, Brown NA. Waves of mouse Lunatic fringe
expression, in four-hour cycles at two-hour intervals, precede somite
boundary formation. Curr Biol 1998; 8:1027–1030.

41. Andrade RP, Palmeirim I, Bajanca F. Molecular clocks underlying
vertebrate embryo segmentation: a 10-year-old hairy-go-round. Birth
Defects Res C Embryo Today 2007; 81:65–83.

42. Rossant J, Zirngibl R, Cado D, Shago M, Giguere V. Expression of a
retinoic acid response element-hsplacZ transgene defines specific
domains of transcriptional activity during mouse embryogenesis. Genes
Dev 1991; 5:1333–1344.

43. Shimozono S, Iimura T, Kitaguchi T, Higashijima S, Miyawaki A.

DOMENICONI ET AL.

6 Article 10

D
ow

nloaded from
 w

w
w

.biolreprod.org. 
D

ow
nloaded from

 https://academ
ic.oup.com

/biolreprod/article-abstract/95/1/10, 1-8/2883479 by U
niversidade Estadual Paulista J�

lio de M
esquita Filho user on 04 July 2019



Visualization of an endogenous retinoic acid gradient across embryonic
development. Nature 2013; 496:363–366.

44. Snyder EM, Small CL, Bomgardner D, Xu B, Evanoff R, Griswold MD,
Hinton BT. Gene expression in the efferent ducts, epididymis, and vas
deferens during embryonic development of the mouse. Dev Dyn 2010;
239:2479–2491.

45. Tomsig JL, Turner TT. Growth factors and the epididymis. J Androl
2006; 27:348–357.

46. Takano H. Qualitative and quantitative histology and histogenesis of the
mouse epididymis, with special emphasis on the regional difference [in
Japanese; author’s transl]. Kaibogaku Zasshi 1980; 55:573–587.

47. Joseph A, Yao H, Hinton BT. Development and morphogenesis of the
Wolffian/epididymal duct, more twists and turns. Dev Biol 2009; 325:
6–14.

48. Tomaszewski J, Joseph A, Archambeault D, Yao HH. Essential roles of
inhibin beta A in mouse epididymal coiling. Proc Natl Acad Sci U S A
2007; 104:11322–11327.

49. Uriu K, Morelli LG. Collective cell movement promotes synchronization
of coupled genetic oscillators. Biophys J 2014; 107:514–526.

50. Xu B, Washington AM, Domeniconi RF, Ferreira Souza AC, Lu X,
Sutherland A, Hinton BT. Protein tyrosine kinase 7 is essential for
tubular morphogenesis of the Wolffian duct. Dev Biol 2016; 412:
219–233.

51. Nie X, Arend LJ. Pkd1 is required for male reproductive tract
development. Mech Dev 2013; 130:567–576.

52. Benson GV, Nguyen TH, Maas RL. The expression pattern of the murine
Hoxa-10 gene and the sequence recognition of its homeodomain reveal
specific properties of Abdominal B-like genes. Mol Cell Biol 1995; 15:
1591–1601.

53. Bomgardner D, Hinton BT, Turner TT. Hox transcription factors may
play a role in regulating segmental function of the adult epididymis. J
Androl 2001; 22:527–531.

54. Bomgardner D, Hinton BT, Turner TT. 50 hox genes and meis 1, a hox-
DNA binding cofactor, are expressed in the adult mouse epididymis. Biol
Reprod 2003; 68:644–650.

55. Hsieh-Li HM, Witte DP, Weinstein M, Branford W, Li H, Small K,
Potter SS. Hoxa 11 structure, extensive antisense transcription, and
function in male and female fertility. Development 1995; 121:
1373–1385.

56. Podlasek CA, Seo RM, Clemens JQ, Ma L, Maas RL, Bushman W.
Hoxa-10 deficient male mice exhibit abnormal development of the
accessory sex organs. Dev Dyn 1999; 214:1–12.

57. Moisan V, Bomgardner D, Tremblay JJ. Expression of the Ladybird-like
homeobox 2 transcription factor in the developing mouse testis and
epididymis. BMC Dev Biol 2008; 8:22.

58. Robaire B, Hinton BT. The epididymis In: Plant T, Zeleznik AJ (eds.),
Knobil and Neill’s Physiology of Reproduction, 4th Ed. New York:
Elsevier; 2015; 691–772.

59. Hahn KL, Beres B, Rowton MJ, Skinner MK, Chang Y, Rawls A,
Wilson-Rawls J. A deficiency of lunatic fringe is associated with cystic
dilation of the rete testis. Reproduction 2009; 137:79–93.

60. Branford WW, Benson GV, Ma L, Maas RL, Potter SS. Characterization
of Hoxa-10/Hoxa-11 transheterozygotes reveals functional redundancy
and regulatory interactions. Dev Biol 2000; 224:373–387.

61. Maclean JA, 2nd, Chen MA, Wayne CM, Bruce SR, Rao M, Meistrich
ML, Macleod C, Wilkinson MF. Rhox: a new homeobox gene cluster.
Cell 2005; 120:369–382.

62. MacLean JA, 2nd, Hayashi K, Turner TT, Wilkinson MF. The Rhox5
homeobox gene regulates the region-specific expression of its paralogs in
the rodent epididymis. Biol Reprod 2012; 86:189.

63. Johnston DS, Jelinsky SA, Bang HJ, DiCandeloro P, Wilson E, Kopf GS,
Turner TT. The mouse epididymal transcriptome: transcriptional
profiling of segmental gene expression in the epididymis. Biol Reprod
2005; 73:404–413.

64. Krutskikh A, De Gendt K, Sharp V, Verhoeven G, Poutanen M,
Huhtaniemi I. Targeted inactivation of the androgen receptor gene in
murine proximal epididymis causes epithelial hypotrophy and obstructive
azoospermia. Endocrinology 2011; 152:689–696.

65. Xie S, Xu J, Ma W, Liu Q, Han J, Yao G, Huang X, Zhang Y. Lcn5
promoter directs the region-specific expression of cre recombinase in
caput epididymidis of transgenic mice. Biol Reprod 2013; 88:71.

66. Bjorkgren I, Gylling H, Turunen H, Huhtaniemi I, Strauss L, Poutanen
M, Sipila P. Imbalanced lipid homeostasis in the conditional Dicer1
knockout mouse epididymis causes instability of the sperm membrane.
FASEB J 2015; 29:433–442.

67. Li Y, Wang HY, Wan FC, Liu FJ, Liu J, Zhang N, Jin SH, Li JY. Deep
sequencing analysis of small non-coding RNAs reveals the diversity of

microRNAs and piRNAs in the human epididymis. Gene 2012; 497:
330–335.

68. Belleannee C, Calvo E, Thimon V, Cyr DG, Legare C, Garneau L,
Sullivan R. Role of microRNAs in controlling gene expression in
different segments of the human epididymis. PLoS One 2012; 7:e34996.

69. Anderson AL, Stanger SJ, Mihalas BP, Tyagi S, Holt JE, McLaughlin
EA, Nixon B. Assessment of microRNA expression in mouse epididymal
epithelial cells and spermatozoa by next generation sequencing. Genom
Data 2015; 6:208–211.

70. Yeung CH, Cooper TG, Bergmann M, Schulze H. Organization of
tubules in the human caput epididymidis and the ultrastructure of their
epithelia. Am J Anat 1991; 191:261–279.

71. Sonnenberg-Riethmacher E, Walter B, Riethmacher D, Godecke S,
Birchmeier C. The c-ros tyrosine kinase receptor controls regionalization
and differentiation of epithelial cells in the epididymis. Genes Dev 1996;
10:1184–1193.

72. Yeung CH, Sonnenberg-Riethmacher E, Cooper TG. Infertile spermato-
zoa of c-ros tyrosine kinase receptor knockout mice show flagellar
angulation and maturational defects in cell volume regulatory mecha-
nisms. Biol Reprod 1999; 61:1062–1069.

73. Yeung CH, Anapolski M, Sipila P, Wagenfeld A, Poutanen M,
Huhtaniemi I, Nieschlag E, Cooper TG. Sperm volume regulation:
maturational changes in fertile and infertile transgenic mice and
association with kinematics and tail angulation. Biol Reprod 2002; 67:
269–275.

74. Yeung CH, Anapolski M, Setiawan I, Lang F, Cooper TG. Effects of
putative epididymal osmolytes on sperm volume regulation of fertile and
infertile c-ros transgenic Mice. J Androl 2004; 25:216–223.

75. Cooper TG, Yeung CH. Acquisition of volume regulatory response of
sperm upon maturation in the epididymis and the role of the cytoplasmic
droplet. Microsc Res Tech 2003; 61:28–38.

76. Jun HJ, Roy J, Smith TB, Wood LB, Lane K, Woolfenden S, Punko D,
Bronson RT, Haigis KM, Breton S, Charest A. ROS1 signaling regulates
epithelial differentiation in the epididymis. Endocrinology 2014; 155:
3661–3673.

77. Sipila P, Cooper TG, Yeung CH, Mustonen M, Penttinen J, Drevet J,
Huhtaniemi I, Poutanen M. Epididymal dysfunction initiated by the
expression of simian virus 40 T-antigen leads to angulated sperm flagella
and infertility in transgenic mice. Mol Endocrinol 2002; 16:2603–2617.

78. Cooper TG, Yeung CH, Wagenfeld A, Nieschlag E, Poutanen M,
Huhtaniemi I, Sipila P. Mouse models of infertility due to swollen
spermatozoa. Mol Cell Endocrinol 2004; 216:55–63.

79. Xu B, Washington AM, Hinton BT. PTEN signaling through RAF1
proto-oncogene serine/threonine kinase (RAF1)/ERK in the epididymis is
essential for male fertility. Proc Natl Acad Sci U S A 2014; 111:
18643–18648.

80. Legare C, Expression Sullivan R. and localization of c-ros oncogene
along the human excurrent duct. Mol Hum Reprod 2004; 10:697–703.

81. Kormano M. Microvascular structure of the rat epididymis. Ann Med
Exp Biol Fenn 1968; 46:113–118.

82. Suzuki F, Nagano T. Microvasculature of the human testis and excurrent
duct system. Resin-casting and scanning electron-microscopic studies.
Cell Tissue Res 1986; 243:79–89.

83. Brown PD, Waites GM. Regional blood flow in the epididymis of the rat
and rabbit: effect of efferent duct ligation and orchidectomy. J Reprod
Fertil 1972; 28:221–233.

84. Suzuki F. Microvasculature of the mouse testis and excurrent duct
system. Am J Anat 1982; 163:309–325.

85. LeBarr DK, Blecher SR. Epididymides of sex-reversed XX mice lack the
initial segment. Dev Genet 1986; 7:109–116.

86. Abe K, Takano H, Ito T. Microvasculature of the mouse epididymis, with
special reference to fenestrated capillaries localized in the initial segment.
Anat Rec 1984; 209:209–218.

87. Clulow J, Hansen LA, Jones RC. In vivo microperfusion of the ductuli
efferentes testis of the rat: flow dependence of fluid reabsorption. Exp
Physiol 1996; 81:633–644.

88. Hess RA. The efferent ductules:structure and functions In: Robaire B,
Hinton BT (eds.), The Epididymis From Molecules to Clinical Practice.
New York: Kluwer Academic/Plenum Publishers; 2002; 49–80.

89. Hirai S, Naito M, Terayama H, Ning Q, Miura M, Shirakami G, Itoh M.
Difference in abundance of blood and lymphatic capillaries in the murine
epididymis. Med Mol Morphol 2010; 43:37–42.

90. Nicander L, Osman DI, Ploen L, Bugge HP, Kvisgaard KN. Early effects
of efferent ductule ligation on the proximal segment of the rat
epididymis. Int J Androl 1983; 6:91–102.

91. Fawcett DW, Hoffer AP. Failure of exogenous androgen to prevent

THE EPIDIDYMIS IS A SERIES OF JOINED ORGANS

7 Article 10

D
ow

nloaded from
 w

w
w

.biolreprod.org. 
D

ow
nloaded from

 https://academ
ic.oup.com

/biolreprod/article-abstract/95/1/10, 1-8/2883479 by U
niversidade Estadual Paulista J�

lio de M
esquita Filho user on 04 July 2019



regression of the initial segments of the rat epididymis after efferent duct
ligation or orchidectomy. Biol Reprod 1979; 20:162–181.

92. Danzo BJ, Cooper TG, Orgebin-Crist MC. Androgen binding protein
(ABP) in fluids collected from the rete testis and cauda epididymidis of
sexually mature and immature rabbits and observations on morphological
changes in the epididymis following ligation of the ductuli efferentes.
Biol Reprod 1977; 17:64–77.

93. Abe K, Takano H, Ito T. Appearance of peculiar multivesicular bodies in
the principal cells of the epididymal duct after efferent duct cutting in the
mouse. Arch Histol Jpn 1984; 47:121–135.

94. Robaire B, Fan X. Regulation of apoptotic cell death in the rat
epididymis. J Reprod Fertil Suppl 1998; 53:211–214.

95. Turner TT, Riley TA. p53 independent, region-specific epithelial
apoptosis is induced in the rat epididymis by deprivation of luminal
factors. Mol Reprod Dev 1999; 53:188–197.

96. Hinton BT, Lan ZJ, Rudolph DB, Labus JC, Lye RJ. Testicular
regulation of epididymal gene expression. J Reprod Fertil Suppl 1998;
53:47–57.

97. Xu B, Washington AM, Hinton BT. Initial segment differentiation begins
during a critical window and is dependent upon lumicrine factors and
SRC proto-oncogene (SRC). Biol Reprod 2016; 95:15.

98. Xu B, Yang L, Lye RJ, Hinton BT. p-MAPK1/3 and DUSP6 regulate
epididymal cell proliferation and survival in a region-specific manner in
mice.Biol Reprod 2010; 83:807–817.

99. Xu B, Abdel-Fattah R, Yang L, Crenshaw SA, Black MB, Hinton BT.
Testicular lumicrine factors regulate ERK, STAT, and NFKB pathways
in the initial segment of the rat epididymis to prevent apoptosis. Biol
Reprod 2011; 84:1282–1291.

100. Hu J, Chen YX, Wang D, Qi X, Li TG, Hao J, Mishina Y, Garbers DL,
Zhao GQ. Developmental expression and function of Bmp4 in
spermatogenesis and in maintaining epididymal integrity. Dev Biol
2004; 276:158–171.

101. Zhao GQ, Liaw L, Hogan BL. Bone morphogenetic protein 8A plays a
role in the maintenance of spermatogenesis and the integrity of the
epididymis. Development 1998; 125:1103–1112.

102. Lan ZJ, Labus JC, Hinton BT. Regulation of gamma-glutamyl
transpeptidase catalytic activity and protein level in the initial segment

of the rat epididymis by testicular factors: role of basic fibroblast growth
factor. Biol Reprod 1998; 58:197–206.

103. Brooks DE. Epididymal functions and their hormonal regulation. Aust J
Biol Sci 1983; 36:205–221.

104. Abe K, Takano H, Ito T. Interruption of the luminal flow in the
epididymal duct of the corpus epididymidis in the mouse, with special
reference to differentiation of the epididymal epithelium. Arch Histol Jpn
1984; 47:137–147.

105. Palladino MA, Hinton BT. Expression of multiple gamma-glutamyl
transpeptidase messenger ribonucleic acid transcripts in the adult rat
epididymis is differentially regulated by androgens and testicular factors
in a region-specific manner. Endocrinology 1994; 135:1146–1156.

106. Wang C, Huang C, Gu Y, Zhou Y, Zhu Z, Biosynthesis Zhang Y. and
distribution of Lewis X- and Lewis Y-containing glycoproteins in the
murine male reproductive system. Glycobiology 2011; 21:225–234.

107. Turner TT. Necessity’s potion: inorganic ions and small organic
molecules in the epididymial lumen In: Robaire B, Hinton BT (eds.),
The Epididymis From Molecules to Clinical Practice. New York: Kluwer
Academic/Plenum Publishers; 2002; 131–150.

108. Hinton BT, Snoswell AM, Setchell BP. The concentration of carnitine in
the luminal fluid of the testis and epididymis of the rat and some other
mammals. J Reprod Fertil 1979; 56:105–111.

109. Rodriguez CM, Labus JC, Hinton BT. Organic cation/carnitine
transporter, OCTN2, is differentially expressed in the adult rat
epididymis. Biol Reprod 2002; 67:314–319.

110. Hinton BT. The testicular and epididymal luminal amino acid
microenvironment in the rat. J Androl 1990; 11:498–505.

111. Breton S, Ruan YC, Park YJ, Kim B. Regulation of epithelial function,
differentiation, and remodeling in the epididymis. Asian J Androl 2016;
18:3–9.

112. Shum WW, Ruan YC, Da Silva N, Breton S. Establishment of cell-cell
cross talk in the epididymis: control of luminal acidification. J Androl
2011; 32:576–586.

113. Robaire B, Hinton BT, Orgebin-Crist MC. The epididymis In: Neill J
(ed.), Knobil and Neill’s Physiology of Reproduction, 3rd ed. St Louis,
MO: Elsevier; 2006; 1071–1148.

DOMENICONI ET AL.

8 Article 10

D
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