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Departments of Pathology (T.R.K., M.M.M.), Cell Biology (M.M.M.), and Molecular and Human Genetics (M.M.M.), Baylor College of Medicine, Houston, Texas 77030; Vollum Institute (M.J.L.), L474, Oregon Health Sciences University, Portland, Oregon 97201
Address all correspondence and requests for reprints to: Martin M. Matzuk, M.D., Ph.D., Baylor College of Medicine, Department of Pathology, One Baylor Plaza, Houston, Texas 77030.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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:ß heterodimeric pituitary glycoprotein that shares a
common -subunit with LH and TSH. To study the role of FSH in
mammalian reproduction, we have previously generated an FSH-deficient
mouse model using embryonic stem (ES) cell technology by introducing a
null mutation in the unique FSHß gene. Male mice deficient in FSH are
fertile despite their small testes and reduced sperm number and
motility. In contrast, FSH-deficient female mice are infertile due to a
block in folliculogenesis at the preantral stage. In this set of
experiments, we have rescued the mutant phenotypes of FSHß-deficient
mice by two genetic strategies. In the type I rescue mice, we
introduced into the FSHß-deficient background a 10-kb human FSHß
transgene that is selectively expressed in pituitary gonadotropes. The
presence of this transgene [and thus the interspecies hybrid
(i.e. mouse :human FSHß hormone)] in the
background of mouse FSHß deficiency completely restored the testis
size, sperm number, and motility defects to levels comparable to those
seen in control male mice. All of the mouse FSHß-deficient female
mice carrying this human FSHß transgene resumed normal
folliculogenesis, were fertile and delivered normal size litters. In
the type II rescue mice, human FSH (human :human FSHß) was
ectopically produced from multiple tissues in the mutant background
using a mouse metallothionein-I promoter. Whereas ectopic production of
human FSH completely rescued the mouse FSHß-deficient male mice, only
3 out of 10 mouse FSHß-deficient females bearing these human FSH
transgenes were fertile and carried their pregnancies to term and
parturition. We conclude that the resultant phenotypes due to a genetic
deficiency of mouse FSHß can be corrected by appropriate expression
of human FSH transgenes and that human FSHß gene regulation and
function in the mouse pituitary are indistinguishable from the
endogenous mouse FSHß gene. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-subunit
with the structurally similar members LH and TSH. The hormone-specific
ß-subunit of each of these hormones is noncovalently linked to the
-subunit and confers the receptor specificity and hence the
biological specificity. The nucleotide and corresponding amino
acid sequences of - and FSHß-subunits from phylogenetically
distant species share significant homology (1, 2). In particular, mouse
FSHß shares 96% similarity and 92% identity with human FSHß at
the amino acid level. Pierce and colleagues first demonstrated that
interspecies hybrids (i.e. the common -subunit from one
species and a unique ß-subunit from others) could be combined
in vitro to yield a functional glycoprotein hormone (3). The
biopotencies of such hybrids were typically measured in an ovarian
ascorbic acid depletion assay (4) or a receptor binding assay (1) using
gonadal membranes. Subsequent biophysical studies have demonstrated
that the association of the gonadotropin subunits follows a very slow
second order kinetics (5, 6). However, it is not known if an
interspecies hybrid can assemble properly, bind the target cell
receptors as efficiently as the corresponding endogenous hormone of a
given species, and elicit similar biological responses in
vivo.
In vertebrates, FSH binds to its cognate receptor on Sertoli cells in
the testis and granulosa cells in the ovary (2). The regulation of both
- and FSHß-subunit gene expression is under stringent control of
the hypothalamic peptide GnRH, gonadal steroids, and gonadal peptides,
including inhibins and activins (7, 8). To directly assess the role of
FSH in gonadal growth and differentiation during mammalian
reproduction, we generated mice with a mutation in the FSHß gene and
hence deficient in FSH using ES cell technology (9). Male mice
deficient in FSH are fertile despite a decrease in testis size and
reduced sperm number and motility. FSH-deficient female mice are
infertile due to a block in the progression of ovarian folliculogenesis
at the preantral stage (9). The FSH-deficient female mice phenocopy a
recessive human genetic disease known as primary amenorrhea. In humans,
a point mutation in the human FSH receptor prevents FSH signaling in
the ovaries of affected female patients (10). Similar to FSH-deficient
male mice, men with this receptor mutation have suppressed sperm number
and decreased testis size but are fertile (11).
Introduction of desired mutations into ES cells and generation of
knockout mice have now become a routine practice. The extent to which
the resultant phenotypes are affected due to such mutations depends on
the fact that no other alterations have occurred elsewhere in the
manipulated mouse genome. To confirm that the reproductive defects in
FSH-deficient mice are only due to an engineered mutation in the mouse
FSHß locus and to determine whether interspecies FSH hybrids can
function properly in vivo, we have now genetically rescued
the FSH-deficient mice in two independent ways (Fig. 1
): 1) by introducing a
pituitary-targeted 10-kb human FSHß transgene, and 2) by ectopically
expressing the human glycoprotein hormone- and human FSHß-subunits
from multiple tissues using 1.8 kb of mouse metallothionein I (mMT-I)
promoter sequences.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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subunit minigene (13) or 5.2 kb of
hFSHß (14) genomic sequences. The human FSHß sequences start at
approximately 200 bp upstream of the transcription initiation site and
include all exons, introns, and approximately 1 kb 3' flanking
sequences. Independent lines of transgenic mice were produced that
carry either the MT-hCG or MT-hFSHß transgene. These were
intercrossed to obtain mice that express both the subunits and hence
hFSH. The serum values of hFSH were monitored (see below) and a
transgenic line of mice expressing hFSH at low levels was chosen to
rescue the fshbm1/fshbm1 mice. The lines of
mice generated in the present study are referred to as type I rescue
mice (FSH-deficient mice rescued with the pituitary targeted hFSHß
transgene) or type II rescue mice (FSH-deficient mice rescued with hFSH
expressed from the metallothionein promoter). In both cases,
fshbm1/fshbm1 male mice were bred to
transgene-bearing female mice to generate fshbm1/+ male and
female mice carrying the transgenes. These were subsequently
intercrossed to obtain homozygous mouse FSH-deficient
(fshbm1/fshbm1) mice carrying the transgene(s).
All mice were maintained and bred in animal facilities at Baylor
College of Medicine under controlled temperature and humidity
conditions. Mice were maintained under 12-h dark, 12-h light cycles
with food and water supplied ad libitum. All studies were
carried out in accordance with the Guide for the Care and Use of
Laboratory Animals as per the NIH instructions as adopted by Baylor
College of Medicine.
Southern blot analysis
All genotype data were generated using Southern blot analysis of
tail DNA samples. The mouse FSHß mutation (fshbm1) was
detected using a 3' probe as described (9). Human FSHß transgenes
were detected using a specific 3' UTR probe (12, 14) and the common
-subunit [human CG -minigene (13)] transgene was detected using
a 700-bp HindIII-HindIII fragment that contains a
portion of intron 3 and exon 4 sequences of the human gene. The
conditions for hybridization and washing were described previously (9, 15).
Histology
Ovaries from adult female mice of various genotypes were
formalin-fixed for at least 48 h. Testes from adult male mice were
fixed in Bouin’s solution for 15–20 h and washed extensively with
LiCO3-saturated 70% ethanol several times. Both the testes
and ovaries were paraffin embedded, and 4-µm sections were cut and
stained with periodic acid Schiff’s reagent and hematoxylin as
described previously (15). The PAS-stained testes sections were scanned
with a Zeiss Axiophot (Carl Zeiss, Göttingen, Germany) microscope
and the images were captured with Adobe Photoshop, version 4.0 graphics
program (Adobe Systems, Inc., San Jose, CA). The cross-sectional areas
of individual tubules were calculated by Digital Image Analysis using
Silicon Graphics-Image Space/Data Manager, version 3.2 software system
(Silicon Graphics, Inc., Mountain View, CA). For each genotype,
multiple testis sections were scanned and measurements of more than 15
independent tubule sections from four different frames were
recorded.
Sperm parameters
Epididymal sperm preparations (from both sides) were made in 1
ml M-2 medium at 37 C as per standard methods (16). Sperm counts and
motility were measured using a hemocytometer, and the viability of
sperm was determined using an eosin-Y method (17).
Serum analysis
Serum levels of human FSH were measured by a fluorometric enzyme
immunoassay (FEIA) using Baxter’s FSH-FEIA kit (Baxter Diagnostics,
Inc., Deerfield, IL) and an automated Stratus fluorometric analyzer
according to the manufacturer’s instructions. The sensitivity of the
assay was 0.3 mIU/ml. The cross-reactivity to LH, TSH, and hCG was
below the 0.5% level.
Statistical analysis
Single factor ANOVA and Student’s t test were
performed using the Microsoft Excel software (Version 4.1) program
(Microsoft Corporation, Redford, WA). A P value of <
0.05 was considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). fshbm1/fshbm1 male mice demonstrate reduced
testis size and a decrease in sperm number and motility compared with
age-matched fshbm1/+ control mice (Ref. 9 and Table 1). To analyze whether the 10-kb hFSHß
transgene could rescue the fshbm1/fshbm1 mice,
testes from adult FR-I male mice were observed morphologically and
histologically (Fig. 2, A–C). The testis
size was restored to that of wild-type or fshbm1/+ control
male mice that carry the transgene. In addition, there was also a
quantitative restoration of the sperm parameters including sperm number
and motility (Table 1). We performed Digital Image Analysis and
measured the cross-sectional area of tubules in the PAS-stained
sections. This analysis, which represents the tubule volume, indicated
that the area of tubules (average ± SEM area) in FR-I
male was comparable with that of control male mice [71.5 ± 5.9 U
(27 tubules) vs. 72.0 ± 2.4 U (19 tubules);
P > 0.05]. In contrast, the average area of tubules
in the testis of fshbm1/fshbm1 mice was found
to be 62% that of FR-I mice [44.2 ± 1.7 U (28 tubules)
vs. 71.5 ± 5.9 U (27 tubules); P <
0.05], consistent with an overall decrease in testis size. There were
no additional differences in the testis histology between FR-I and
control male mice, including Leydig cell number (data not shown).
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, D–F). The ovarian histology of
FSH-deficient mice demonstrates limited progression of
folliculogenesis. No normal antral or later stage follicles are seen,
but primordial and preantral follicles are observed with apparently
normal theca, granulosa layers, and oocytes (9). In contrast,
histological examination of the ovaries obtained from FR-I adult female
mice showed normal stages of folliculogenesis including the presence of
antral follicles and preovulatory follicles. In addition, there were
obvious corpora lutea (Fig. 2F), suggesting that the presence of the
human FSHß transgene restored the estrous cycle to normal.
Furthermore, in contrast to the complete infertility of the
fshbm1/fshbm1 female mice, 6 out of 6 breeding
FR-I female mice produced normal size litters (9.6 ± 0.7
pups/litter; n = 18 litters) and viable offspring. Thus, these
results demonstrate that gonadotrope-targeted expression of a 10-kb
hFSHß gene in the fshbm1/fshbm1 mutant
background results in the formation of an interspecies FSH hybrid
(mouse :human FSHß) that can completely restore the fertility and
rescue the reproductive defects of mice deficient in the mouse FSHß
subunit.
Complete restoration of the wild-type phenotype in male but not
female type II rescue mice
Bi-transgenic (MT-human FSH) mice that harbor an mMT-1 driven
hCG- minigene and an mMT-1 driven human FSHß transgene were
produced by mating of the independent lines of transgenic mice that
express these subunits in multiple tissues (data not shown). The
absence of gonadotrope-specific expression of the hFSHß subunit was
confirmed by dual immunofluorescence (using a hFSHß-specific
monoclonal antibody and rat LHß polyclonal antiserum), and by RT-PCR
analysis of individual pituitary total RNA using hFSHß 3'
UTR-oligonucleotides (data not shown). The production of dimeric hFSH
in the serum of these mice was confirmed by a hFSH-specific
fluoroimmunoassay. The serum hFSH values in adult males and females
were 48.0 ± 5.3 (n = 5) and 115.9 ± 24.4 (n = 5),
respectively, and would not be expected to be pulsatile (MT-1 promoter
is constitutively active). These mice were fertile and did not show any
overt phenotypes up to 1 yr of age. MT-hFSH+ (i.e. both
MT-CG and MT-hFSHß transgene bearing) female mice were bred to
fshbm1/fshbm1 male mice; fshbm1/+,
MT-hFSH+ mice were obtained and were intercrossed to generate
fshbm1/fshbm1, MT-hFSH+ (FR-II) mice.
The presence of the MT-hFSH transgenes both qualitatively (testis size)
and quantitatively (sperm number and motility) restored the wild-type
phenotype in male FR-II mice (Fig. 3, A–C and Table 2), similar to the FR-I
male mice. Digital Image Analysis was performed to measure the
cross-sectional area of tubules from PAS-stained sections of FR-II and
control male mice. Similar to FR-I male mice, the average ±
SEM cross-sectional area of tubules from FR-II male mice
was comparable with that of control male mice and is significantly
different when compared with that from the testis of
fshbm1/fshbm1 mice (78.6 ± 8.2 U (22
tubules) vs. 44.2 ± 1.7 U (28 tubules);
P < 0.05].
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)]. The majority of these nonrescued FR-II female mice also
had thin uteri. However, histological analysis revealed that ovaries
from one of the fertile FR-II female mice that became pregnant and
delivered one litter had an obvious corpus luteum and also small antral
follicles (Fig. 3, E and F). Therefore, these results suggest that
ectopically produced hFSH can restore the phenotypes completely in male
but only incompletely in female FR-II mice. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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: human FSHß) is biologically equivalent to mouse
FSH. In addition, these in vivo data also lend support to
the notion from previous in vitro studies that
receptor-specific epitopes on FSHß-subunits are conserved between
mammalian species (20). Thus, by targeting species-specific FSHß
transgenes to pituitary gonadotropes in the mouse FSH-deficient
background (i.e. using FSHß knockout mice), one could
estimate in vivo the differences in biopotency of FSHß
subunits of different species heterodimerized with the endogenous mouse
-subunit.
It is known that mMT-1 the promoter is active in multiple tissues (21).
In the type II rescue mice, we have targeted the human -glycoprotein
hormone and human FSHß-subunit genes to multiple tissues using a
mMT-1 promoter and introduced these transgenes into the mouse
FSH-deficient background. This ectopic expression of human FSH also
restored the normal testicular phenotypes both qualitatively and
quantitatively in male FR-II mice. Although at low frequency (30%),
the FR-II female mice could also be rescued because three of these
females became pregnant and delivered their litters. However, we do not
know if the sustained and constitutive ectopic (nonpulsatile)
expression of human FSH in some way caused the lethality of the FR-II
female mice (2 of the 3) that became pregnant and successfully
delivered their litters. The reason for the differences in fertility
between individual FR-II female mice is unclear. It may perhaps be due
to individual differences in gonadal response(s) to prolonged
exposure to hFSH. Along with the type I rescue data, these
results suggest that for normal progression of ovarian
folliculogenesis, FSH released from the pituitary in a pulsatile manner
appears to be more efficient than ectopically produced FSH in a
nonpulsatile manner. The genetic rescue of FR-I and FR-II female mice
is consistent with our previous hCG/PMSG-induced superovulation data
confirming that the ovulatory competence is unaffected in the complete
absence of FSH in fshbm1/fshbm1 mice (9). The
genetic rescue experiments provided the final formal proof that the
reproductive abnormalities of fshbm1/fshbm1
mice are caused by the purposefully engineered mutation in the mouse
FSHß gene.
Several types of in vitro bioassays have been developed to test different FSH analogs and isoforms. These include measurement of steroids (22, 23) or cAMP (24) or reporter gene expression using cells or cell lines from different species (25, 26). Our present results based on a genetic rescue suggest that FSHß-deficient mice can be successfully used as an in vivo bioassay to test the bioactivity of various human FSH isoforms and analogs. By injecting various FSH analogs, increments in testicular size, and quantitative analysis of sperm parameters (such as sperm number and motility) or scoring the progression of ovarian folliculogenesis beyond antrum formation can be reliably monitored in a homogeneous (i.e. FSHß-deficient) genetic background.
Mammalian reproduction is a complex physiological process involving interactions between diverse factors secreted from the hypothalamic-pituitary-gonadal axis (27, 28). The fact that the reproductive defects in FSH-deficient mice could be successfully rescued by FSH transgenes further emphasizes the power of introducing mutations by a gene-targeting approach into specific loci without any global-perturbations in the mouse genome.
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Acknowledgments |
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minigene, and Dr.
Richard Palmiter for the gift of the mouse metallothionein I promoter
sequences. We thank Dr. Mike A. Mancini for helping us with the Digital
Image Analysis. |
Footnotes |
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Received December 4, 1997.
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References |
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- and ß-subunits on the
kinetics of formation and activity of native and hybrid molecules of LH
and human chorionic gonadotropin. Endocrinology 93:938–946-Inhibin is a tumor-suppressor gene with gonadal
specificity in mice. Nature 360:313–319[CrossRef][Medline]
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