Endocrinology Vol. 140, No. 5 2084-2088
Copyright © 1999 by The Endocrine Society
High Specificity of Müllerian-Inhibiting Substance Signaling in Vivo1
Yuji Mishina2,
Deanne J. Whitworth,
Chrystèle Racine and
Richard R. Behringer
Department of Molecular Genetics (Y.M., D.J.W., R.R.B.), The
University of Texas M. D. Anderson Cancer Center, Houston, Texas
77030; Unité de Recherches sur l’Endocrinologie du
Développement (C.R.), INSERM U. 493, École Normale
Supérieure, Département de Biologie, 92120 Montrouge,
France
Address all correspondence and requests for reprints to: Department of Molecular Genetics, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030. E-mail:
bhr{at}molgen.mda.uth.tmc.edu
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Abstract
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Female transgenic mice that ectopically express high levels of human
Müllerian-inhibiting substance (hMIS) under the control of the
mouse metallothionein (MT) promoter lack a uterus, oviducts, and
ovaries. The loss of the uterus and oviducts is consistent with the
known activities for MIS. However, it is not clear if the loss of the
ovaries in these transgenic females is caused by interactions of MIS
with its normal receptor signaling pathway or by abnormal interactions
with other transforming growth factor-ß (TGF-ß) super family
receptor signaling pathways. To address this question, female mice
carrying the MT-hMIS transgene that were also homozygous for a targeted
deletion of the MIS type II receptor gene were generated. Although
these females had high levels of circulating hMIS, they had normal
reproductive tracts and ovaries with germ cells. In addition, these
females were able to become pregnant and gave birth to pups. These
findings demonstrate that all of the abnormalities of the reproductive
system that are found in female transgenic mice that ectopically
express high levels of hMIS are caused by signaling through the MIS
type II receptor. These in vivo data demonstrate a high
specificity for MIS and its receptor. 140: 2084–2088, 1999)
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Introduction
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MÜLLERIAN-INHIBITING SUBSTANCE (MIS),
also known as anti-Müllerian hormone (AMH) causes the regression
of the Müllerian ducts—the anlagen of the uterus, oviducts, and
the upper portion of the vagina—in the male fetus (1). MIS is produced
by the Sertoli cells of the fetal testis (2). In the mouse, MIS
transcripts are first detected by RNase protection assays in the fetal
testes at embryonic day 11.5 (E11.5) (3). MIS levels are highest during
male fetal development and continue after birth in the postnatal testes
then decline significantly at the time of puberty (4, 5, 6, 7). MIS is also
expressed in females but only after birth in the granulosa cells of the
ovary (5, 8, 9, 10). In the mouse, MIS transcripts are initially detected
by in situ hybridization in the ovary at 6 days after birth
(5). In addition to its established role in Müllerian duct
regression, MIS has also been suggested to regulate gametogenesis and
testicular descent (11, 12, 13, 14).
Experiments to examine the role of MIS in vivo have been
performed in transgenic mice that were generated by pronuclear
injection of fertilized eggs (15). The mouse metallothionein promoter
was used to widely express high levels of hMIS in both males and
females during development. Most of the male MT-hMIS transgenic mice
were phenotypically normal and fertile. However, some males with very
high levels of MIS did not virilize, suggesting a deficiency of
androgens. This was subsequently confirmed by Lyet et al.
(16) who determined that all MT-hMIS transgenic males have reduced
levels of serum testosterone in comparison to nontransgenic controls.
Recently, Leydig cells have been shown to express the MIS receptor,
demonstrating that MIS signaling can directly regulate Leydig cell
function (17, 18).
Nearly all of the female MT-hMIS transgenic mice had abnormalities of
the reproductive tract. The consistent mutant phenotype among these
transgenic females was the complete absence of a uterus and oviducts.
In addition, ovaries were also absent. It was demonstrated that ovaries
initially developed in the MT-hMIS females but soon after birth germ
cells were lost and subsequently the somatic cells of the ovary
reorganized into structures resembling seminiferous tubules (15, 16).
Ultimately, these abnormal gonads degenerated because they were not
found in adult MT-hMIS females. Thus, high levels of MIS can cause
ovarian degeneration in postnatal transgenic mice. Ovarian degeneration
is also observed in the bovine freemartin that has been exposed to
ectopic MIS by chorioallantoic fusion with its male twin’s placenta
(19, 20).
The essential roles for MIS have been defined by analyzing patients
with Persistent Müllerian Duct Syndrome (PMDS) who have MIS
ligand and MIS type II receptor gene mutations (21, 22, 23, 24, 25, 26) and by
analyzing MIS ligand and MIS type II receptor mutant mice generated by
targeted mutagenesis using embryonic stem (ES) cells (27, 28). In both
human and mouse, males that lack MIS or its type II receptor retain
Müllerian duct-derived tissues and develop as internal
pseudohermaphrodites. In the mouse MIS and MIS type II receptor
mutants, Leydig cell hyperplasia was also observed. Spermatogenesis
appears to be normal in MIS- and MIS type II receptor-deficient mice.
Indeed, their sperm are capable of fertilizing eggs to produce progeny.
Whereas germ cells are present in the testicular biopsies of young
children with PMDS with cryptorchidism, the germ cells begin to decline
at 2 years of age and by puberty are absent (29). In contrast,
testicular descent in MIS and MIS type II receptor mutant mice is
normal. Species-specific anatomical differences may account for these
divergent phenotypes in testicular descent. Although MIS is expressed
in granulosa cells at precise stages of folliculogenesis, no
abnormalities have been detected in MIS-deficient females or MIS type
II receptor-deficient females. Thus, there is no in vivo
evidence for an essential role for MIS in the ovary.
To determine if the reproductive system abnormalities observed in
female MT-hMIS transgenic mice are caused only by MIS signaling through
the MIS receptor, we generated females that carried the MT-hMIS
transgene that were also homozygous for the MIS type II receptor
mutation that blocks MIS signaling. These females proved to be normal
and fertile, demonstrating that the reproductive tract and ovarian
lesions caused by high level, ectopic hMIS are mediated by the MIS
receptor and not by other transforming growth factor (TGF)-ß super
family receptors. These in vivo findings demonstrate a high
specificity for the interactions between the MIS ligand and its type II
receptor.
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Materials and Methods
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Mice
The 1789–1 line of MT-hMIS transgenic mice was used for this
study (15). This transgenic mouse line has been maintained by repeated
backcrosses to C57BL/6 (B6). MT-hMIS transgenic mice were identified by
Southern blot analysis using a hMIS-specific probe (15). The MIS type
II receptor mutant mice used in this study have been maintained on a B6
x 129/SvEv mixed genetic background (28). The MIS receptor mutant
allele was identified by Southern blot analysis as previously described
(28).
Serum MIS assay
Human MIS was measured in mouse serum using the AMH/MIS
enzyme-linked immunoabsorbent assay (ELISA) kit
(Immunotech-Coulter, Marseille, France). Briefly,
25 µl of each serum sample was incubated in duplicate on a
polystyrene plaque precoated with a monoclonal anti-hMIS antibody.
After a 1-h incubation, a second monoclonal anti-hMIS antibody coupled
to biotin was added together with a streptavidin-horseradish peroxidase
complex. After addition of TMBTM substrate, the resulting color
reaction was quantified using a MRX spectrophotometer (Dynatech Corp., Chantilly, VA) at 450 nm. A preparation of purified
recombinant hMIS was used to construct a standard curve. The limit of
sensitivity of the assay was 0.7 pmol/liter (0.1 ng/ml), interassay and
intraassay coefficients of variation were 8.7% and 5.3%,
respectively, for a serum hMIS concentration of 35 pmol/liter and 7.8%
and 4.9% for a serum hMIS concentration of 1100 pmol/liter. No
cross-reaction was observed with pure TGF-ß.
Histology
The female reproductive tracts were immersed in 10%
neutral-buffered formalin, embedded in paraffin, and sectioned at 7
µm. The tissue sections were stained with hematoxylin and eosin.
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Results
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Generation of MT-hMIS; MIS type II receptor-deficient female
mice
The breeding strategy to generate females carrying the MT-hMIS
transgene that were also homozygous for the targeted MIS type II
receptor mutation is shown in Fig. 1
.
This particular breeding strategy was used because MT-hMIS transgenic
females and MIS type II receptor homozygous mutant males are sterile
(15, 28). Initially, males hemizygous for the MT-hMIS transgene were
bred with females that were homozygous for the MIS type II receptor
mutation. Male progeny from this cross that were hemizygous for the
MT-hMIS transgene and also heterozygous for the MIS type II receptor
mutation were identified by Southern blot analysis. These males were
then bred with females that were either heterozygous or homozygous for
the MIS type II receptor mutation. Female progeny from these crosses
that were hemizygous for the MT-hMIS transgene and homozygous for the
MIS type II receptor mutation were identified. Females that were
hemizygous for the MT-hMIS transgene and wild-type or heterozygous for
the MIS type II receptor mutation served as age and genetic background
matched controls. Age matched wild-type females were also used as
controls.
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Figure 1. Breeding scheme to generate female MT-hMIS
transgenic mice that are MIS type II receptor deficient. MIS-RII, MIS
type II receptor; +/+, wild-type; -/-, homozygous mutant. Not all
possible genotypes for these crosses are indicated.
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Previously, the 1789–1 line of MT-hMIS transgenic mice has been shown
to express approximately 225 ng/ml (range 36–500) of hMIS in the
plasma of adult males and females (15). To verify that the MT-hMIS
transgene was active in all three genotypic classes of MT-hMIS; MIS
type II receptor mice, serum hMIS levels were quantified by a
noncompetitive, solid-phase, double-antibody enzyme-linked
immunoabsorbent assay (Table 1). Consistent with our
previous studies, all three genotypic classes of MT-hMIS; MIS type II
receptor mice expressed hMIS at levels comparable to the parent
transgenic mouse line that has been shown to be sufficient for the
elimination of the female reproductive tract and ovaries (15).
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Table 1. Levels of human MIS in MT-hMIS transgenic females
that are wild-type, heterozygous, or homozygous for the MIS type II
receptor mutation
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Reproductive tract and ovarian development in MT-hMIS; MIS type II
receptor-deficient female mice
The reproductive tracts of females that were hemizygous for
the MT-hMIS transgene and heterozygous or homozyxgous for the MIS type
II receptor mutation were examined for gross morphology in comparison
with wild-type controls (Fig. 2, A–C). MT-hMIS transgenic females that were heterozygous
for the MIS type II receptor mutation lacked a uterus, oviducts, and
ovaries, functionally demonstrating the presence of ectopic MIS
activity (Fig. 2B). These reproductive abnormalities are the same as
those previously documented for this transgenic mouse line (15). This
line has some variability in phenotype, including a low frequency of
incompletely regressed Müllerian duct tissue and ovaries in
various states of degeneration (15). In contrast, all MT-hMIS
transgenic females that were homozygous for the MIS type II receptor
mutation had a uterus, oviducts and ovaries that appeared grossly
normal (Fig. 2C).
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Figure 2. Adult reproductive tract morphology and ovarian
histology. A–C, Gross morphology of female reproductive tracts. D–F,
Histological examination of ovaries stained with hematoxylin and eosin.
A and D, wild-type. B and E, MT-hMIS; MIS type II receptor
heterozygote. C and F, MT-hMIS; MIS type II receptor homozygous mutant.
Arrowhead, ovary; arrow, uterine horn; B, bladder. In the MT-hMIS; MIS
type II receptor heterozygote shown in panel E, a remnant of an ovary
is present with three antral follicles and a large fluid-filled cyst.
However, most adult females of this genotype had no detectable ovarian
tissue. In contrast, the MT-hMIS; MIS type II receptor homozygous
mutant shown in panel F has normal ovarian morphology.
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The ovaries from the female mice described above were also
examined by histology (Fig. 2
, D–F). The ovaries, if present, from
MT-hMIS transgenic females that were heterozygous for the MIS type II
receptor mutation were mostly degenerate with few surviving follicles
(Fig. 2E). In contrast, the ovaries from the MT-hMIS transgenic females
that were homozygous for the MIS type II receptor mutation were normal
with follicles at all stages of development (Fig. 2F).
Because the reproductive tracts and ovaries of the MT-hMIS transgenic
females that were homozygous for the MIS type II receptor mutation
appeared normal, we bred these females with nontransgenic males.
Females with this genotype became pregnant and gave birth to normal
numbers of pups, demonstrating that the reproductive system of these
females were functionally normal.
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Discussion
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Female transgenic mice that ectopically express high levels of
hMIS have multiple abnormalities that are specifically limited to the
reproductive system (15, 16). As one might expect for the action of
MIS, the Müllerian duct derivatives, including the uterus,
oviducts, and the upper portion of the vagina are absent in these
female transgenic mice. In addition, there was also ovarian
degeneration. This ovarian degeneration occurs soon after birth and is
characterized by the initial loss of germ cells, followed by the
reorganization of the somatic cells into seminiferous tubule-like
structures and the eventual loss of the gonad (15). How MIS caused the
loss of the ovary in female MT-hMIS transgenic mice was not clear from
initial studies.
The MIS type II receptor is unique among the TGF-ß super family
receptors. First, it is expressed in a highly tissue-specific pattern
during development and in adult tissues (30, 31, 32, 33, 34). In addition, mice and
humans with mutations in the MIS type II receptor gene phenocopy those
with mutations in the MIS ligand gene (26, 27, 28). These findings indicate
that MIS is the only ligand that interacts with the MIS type II
receptor. However, it is not clear if ectopic interactions with other
TGF-ß super family receptors might occur in the presence of high
levels of MIS. To test this, we generated female MT-hMIS transgenic
mice that lacked the MIS type II receptor.
Female MT-hMIS transgenic mice that lacked the MIS type II receptor had
normal reproductive tracts and were capable of carrying a pregnancy to
term even with high levels of circulating hMIS. Thus, our results
suggest that all of the reproductive abnormalities, including the
degeneration of the ovaries, of female MT-hMIS transgenic mice are
caused by MIS signaling through the MIS type II receptor. Furthermore,
these results indicate that even in the presence of very high levels of
hMIS, other TGF-ß family receptor signaling pathways are apparently
not activated (Fig. 3). Thus, the MIS signaling pathway exhibits very
high ligand-receptor specificity, and cross-talk among other related
receptors is likely to be nonexistent.
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Figure 3. Summary of MT-hMIS, MIS type II receptor
transgenic mouse study. Female MT-hMIS transgenic mice lack a uterus
and oviducts. The Müllerian duct regression in these females is
caused by the ectopic expression of hMIS during fetal development. In
addition, there is a postnatal loss of germ cells that subsequently
leads to ovarian degeneration. The excess human MIS expressed from the
MT-hMIS transgene does not cross-talk with other TGF-ß family
receptors. All MIS signals are transduced through the MIS type II
receptor for Müllerian duct regression and female germ cell loss.
Granulosa cells of the ovary express the MIS type II receptor.
Therefore, the mechanism by which MIS signaling causes germ cell loss
is likely to be indirect. Perhaps excessive MIS signaling in granulosa
cells alters their ability to support germ cell development.
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Granulosa cells of the postnatal ovary express MIS, which is
compatible with normal ovarian function and germ cell development. The
granulosa cells also express the MIS type II receptor (30, 31, 32, 34),
suggesting an autocrine function for MIS in granulosa cells of the
ovary. It is currently not clear if female germ cells express the MIS
type II receptor. Thus, it cannot formally be excluded that MIS acts
directly on germ cells. However, our results seem to be most simply
explained by the idea that excess MIS signaling in granulosa cells
indirectly retards meiotic development of the germ cells (16). The
subsequent degeneration of ovarian tissue in female MT-hMIS transgenic
mice may be a nonspecific response to the loss of germ cells caused by
excessive MIS signaling (35). It will be interesting to explore the
molecular differences between granulosa cells with normal and abnormal
MIS signaling to determine how these differences alter female germ cell
development.\.
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Acknowledgments
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We are grateful to Soazik Jamin, Nathalie Josso, and Rodolfo Rey
for helpful comments on the manuscript.\.
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Footnotes
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1 These studies were supported by a National Institutes of Health Grant
(HD-30284) (to R.R.B.). 
2 Present address: National Institute of Environmental Health
Sciences/National Institutes of Health, Laboratory of Reproductive and
Developmental Toxicology, 111 T. W. Alexander Drive, Research
Triangle Park, North Carolina 27709.
Received October 20, 1998.
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Top
Abstract
Introduction
