1 Division of Endocrinology and Department of Medicine, Northwestern University
Feinberg School of Medicine, Chicago, IL 60611, USA
2 Division of Endocrinology and Medicine and Department of Internal Medicine,
University of Michigan, Ann Arbor, MI 48109, USA
* Author for correspondence (e-mail: ljameson{at}northwestern.edu)
Accepted 16 March 2005
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SUMMARY |
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Key words: Sf1, Dax1, Gonad, Mouse embryo, Nuclear receptor
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Introduction |
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Dax1 is atypical among nuclear receptors because it lacks the highly
conserved zinc-finger DNA-binding domain
(Zanaria et al., 1994).
Instead, the amino terminus of Dax1 contains a repeated peptide sequence
comprising variations of a hydrophobic LXXLL-like motif
(Zhang et al., 2000
) that
mediates protein-protein interactions
(Suzuki et al., 2003
). Dax1
may bind to certain DNA hairpin structures and to RNA
(Lalli et al., 2000
), but its
major transcriptional regulatory action involves direct interactions with
other nuclear receptors, including Sf1
(Holter et al., 2002
;
Ito et al., 1997
;
Zhang et al., 2000
). The
carboxy terminus of Dax1 contains a transcriptional repressor domain
(Ito et al., 1997
;
Zazopoulos et al., 1997
) that
interacts with several different co-repressors
(Altincicek et al., 2000
;
Crawford et al., 1998
). One
model of Sf1 and Dax1 action proposes that the N terminus of Dax1 interacts
with Sf1, and recruits repressors to the Sf1 transcription complex, thereby
inhibiting the expression of Sf1-regulated genes such as Star, Dax1, Lhb,
3ßHSD (Hsd3b Mouse Genome Informatics),
Cyp19, Cyp11a1 and Amh
(Lalli et al., 1998
;
Nachtigal et al., 1998
;
Salvi et al., 2002
;
Suzuki et al., 2003
;
Tabarin et al., 2000
;
Wang et al., 2001
;
Zazopoulos et al., 1997
).
Sf1 is expressed in the urogenital ridge at E9.5
(Ikeda et al., 1994;
Ikeda et al., 2001
). In the
male gonad, Sf1-positive cells can be found in a population of coelomic
epithelial cells that give rise to both Sertoli and interstitial cell
precursors (Schmahl et al.,
2000
). In the Sertoli population, one target of Sf1 is
anti-Müllerian hormone (Amh/Mis)
(Hatano et al., 1994
;
Shen et al., 1994
). Later in
testis development, Sf1 expression intensifies in the interstitial
Leydig population where it regulates the expression of multiple steroidogenic
enzyme genes necessary for testosterone production
(Hatano et al., 1994
;
Ikeda et al., 1996
;
Morohashi et al., 1993
).
Dax1 expression peaks in the male gonad at E11.5 and then remains
relatively low until E17.5 when it increases significantly
(Ikeda et al., 2001
). At
E11.5, Sf1 and Dax1 proteins overlap in the XY bipotential gonad, and by
E12.5, they are co-localized mainly within the testis cords
(Ikeda et al., 2001
). The
spatial and temporal overlap of Sf1 and Dax1 expression
during the crucial time of gonadal differentiation raises the possibility of a
functional interaction, but this has not been explored directly in vivo.
Loss-of-function mutations in Sf1 and Dax1 suggest
important roles in gonadal development. Homozygous deletion of Sf1 in
mice prevents adrenal gland and gonadal development, reflecting increased
programmed cell death in the cell populations that normally give rise to these
tissues (Luo et al., 1994). In
the male, the failure of testis differentiation results in absence of
anti-Müllerian hormone production and, consequently, there is persistence
of Müllerian structures at birth. Prior to regression of the gonad
rudiment in the Sf1 homozygous knockout, primordial germ cells are
detectable in the gonadal ridge (Luo et
al., 1994
). Thus, the primary role of Sf1 in gonad
development involves the somatic cell lineages.
Dax1-null hemizygous male mice have testicular dysgenesis and
delayed regression of the fetal X-zone in the adrenal gland
(Yu et al., 1998b). Although
Dax1 had been suggested as a possible ovarian determining gene,
ovaries develop in females with deletion of Dax1 on both X
chromosomes. Adult female mice lacking Dax1 exhibit multi-oocyte
follicles but they are fertile. The loss of Dax1 function in the
testis has been shown to impair testis cord formation. This is caused in part
by reduced numbers of peritubular myoid (PTM) cells
(Meeks et al., 2003a
), which
normally surround the testis cords and, together with Sertoli cells, form the
basement membrane of the developing seminiferous tubules. In the adult, the
efferent duct epithelium is hyperplastic and there is obstruction of
seminiferous tubules (Jeffs et al.,
2001
). Sertoli cells appear to be incompletely differentiated and
germ cells progressively degenerate. As a consequence, male Dax1 null
mice are infertile. Leydig cell development is also altered in the absence of
Dax1. Fetal Leydig cells are restricted to the coelomic side of the
interstitial compartment rather than extending across the full diameter of the
gonad (Meeks et al., 2003a
).
In the adult, Leydig cells are hyperplastic and aromatase expression is
elevated, leading to increased intratesticular estradiol production
(Wang et al., 2001
). On a
genetic background with a weakened Sry allele (Mus domesticus
poschiavinus), the phenotype associated with Dax1 deletion
changes from dysgenetic testes to complete sex reversal
(Meeks et al., 2003b
),
indicating that Dax1 functions in parallel with, or downstream of,
Sry in the sex determination cascade to mediate normal testis
development. Thus, Dax1 plays a more crucial role in testis
differentiation than it does in ovary development.
Dax1-deficient mice exhibit overactivity of some Sf1-regulated
genes, consistent with the idea that Dax1 antagonizes Sf1 function. For
example, Cyp19, an Sf1-regulated steroidogenic enzyme gene, is
overexpressed in the testis of adult male Dax1-knockout mice
(Wang et al., 2001).
Cyp21, a key enzyme for mineralocorticoid and glucocorticoid
synthesis, is overexpressed in the adrenal gland of Dax1-deficient
mice (Babu et al., 2002
). These
findings are consistent with a model in which Dax1 represses Sf1-mediated
transcription.
The phenotypes seen in Sf1 and Dax1 knockout mice are
largely predictive of the clinical manifestations in humans with mutations in
SF1 or DAX1 (Achermann et
al., 2001b). SF1 mutations cause adrenal insufficiency
and XY gonadal dysgenesis. These features occur even with heterozygous
mutations and vary across a wide phenotypic spectrum
(Jameson, 2004
). Thus, in
humans, the function of SF1 is strikingly dose dependent
(Achermann et al., 2002
). Human
DAX1 mutations cause X-linked adrenal insufficiency, hypogonadotropic
hypogonadism and gonadal dysgenesis
(Bardoni et al., 1994
;
Muscatelli et al., 1994
;
Zanaria et al., 1994
). Some
mutations with partial loss of DAX1 activity are associated with
delayed onset and milder clinical features
(Ozisik et al., 2003b
;
Salvi et al., 2002
;
Tabarin et al., 2000
),
suggesting that DAX1 action is also dose dependent
(Achermann et al., 2001a
;
Reutens et al., 1999
).
The phenotypic similarities associated with Sf1 and Dax1
loss-of-function mutations are somewhat at odds with their proposed
antagonistic actions at the transcriptional level. To further explore their
functional relationship in vivo, we examined testis development in the context
of combined loss of function of Sf1 and Dax1. We
hypothesized that Sf1 heterozygosity would reduce the expression of
some Sf1 target genes, such as steroidogenic enzymes genes
(Lala et al., 1992;
Morohashi et al., 1992
).
Moreover, because Dax1 acts as a repressor of Sf1-mediated transcription
(Ito et al., 1997
;
Lalli et al., 1997
), we
predicted that Dax1 deficiency might partially or completely
compensate for Sf1 heterozygosity in the Sf1/Dax1 double
mutant. In contrast to a model in which Dax1 acts as a universal
antagonist of Sf1 action, combined loss of Sf1 and
Dax1 further impaired Sertoli cell differentiation and fetal Leydig
cell development. In the embryonic gonad, we found that Sf1 and
Dax1 act coordinately to enhance the expression of the
Sertoli-derived factors Dhh and Amh. Dhh is a paracrine
signaling factor that regulates fetal Leydig cell development
(Yao et al., 2002
). Amh is a
key regulator of Müllerian regression and testis differentiation
(Behringer et al., 1990
;
Behringer et al., 1994
;
Ross et al., 2003
;
Vigier et al., 1985
). Thus
early male gonadal development depends on the cooperative function of
Sf1 and Dax1.
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Materials and methods |
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In situ hybridization
In situ hybridization was performed by a standard protocol
(Wilkinson, 1998). Plasmid
constructs for synthesis of probes to detect Amh, Sox9; Cyp11a1,
Cyp17; and Dhh were generously provided by B. Capel (Duke
University), P. Koopman (University of Queensland), S. Tevosian (Dartmouth
College) and A. McMahon (Harvard University), respectively. Whole-mount tissue
was viewed with a Leica MZLFIII (Leica, Heerbrugg, Switzerland) dissecting
microscope and images were taken with a Color MagnaFire (Optronics, Goleta,
CA) digital camera. Littermates were used as wild-type controls.
TUNEL apoptosis detection
Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling
(TUNEL) of fragmented DNA in apoptotic cells on tissue sections of embryonic
gonads was performed using the Fluorescein-FragEL kit (Calbiochem, San Diego,
CA) according to the manufacturer's instructions. De-paraffinized sections
were treated with Proteinase K. Incubation with terminal deoxynucleotidyl
transferase catalyzed the addition of fluorescein-labeled deoxynucleotides to
exposed 3'-OH ends of DNA fragments. Nuclei were counterstained with
Propidium Iodide mounting medium (Vector Laboratories, Burlingame, CA).
Fluorescence microscopy images were captured on a Zeiss Axioskop (Zeiss,
Thornwood, NY) with a Color MagnaFire (Optronics, Goleta, CA) digital
camera.
Immunohistochemistry
Paraffin wax-embedded tissue was sectioned at 5 µm using a Jung RM 2025
(Leica, Nussloch, Germany) microtome. Sections were deparaffinized by serial
washes in xylenes and ethanol, followed by antigen retrieval in sodium citrate
buffer (pH 6.0) at high temperature. 3ß-hydroxysteroid dehydrogenase
antibody (1:2500) was provided by Ian Mason (Edinburgh, Scotland). Secondary
antibodies were applied for two hours at room temperature (Goat
Cy3-anti-rabbit from Jackson Immunoresearch, West Grove, PA, DAB Vector,
Burlingame, CA). Sections were washed and mounted with DAPI Hard Set (Vector,
Burlingame, CA). Hematoxylin (Fisher Scientific, Fairlawn, NJ) and Eosin
(Surgipath, Richmond, IL) (H&E) staining was performed following
de-paraffinization of tissue and xylene-to-ethanol washes. Sections were
viewed with a Zeiss Axioskop. Pictures were taken with a Color MagnaFire
(Optronics, Goleta, CA) digital camera.
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Results |
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Discussion |
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In this study, the dose-dependent effects of Sf1 seen previously
in the adrenal gland (Babu et al.,
2002; Bland et al.,
2004
; Bland et al.,
2000
) were also found in the developing testis. Heterozygous
Sf1 mice have delayed adrenal development and reduced adrenal size
but adrenal function is ultimately normal, indicating that compensatory
mechanisms activate Sf1 target genes and stimulate adrenal growth. In the
developing testis, heterozygous Sf1 mice have reduced expression of
Leydig and Sertoli marker genes but these cell types recover, indicating a
transient delay when Sf1 expression is reduced. The effects of
Sf1 deficiency in the early stage of gonad development are more
pronounced in the periphery of the gonad than in the central region.
Immunohistochemical analyses have shown that Sf1 is expressed
throughout the developing bipotential gonad at 11.5 dpc
(Ikeda et al., 2001
). In the
coelomic epithelial layer of the male gonad, a population of Sf1-positive
cells are proliferative and contribute to the sexually dimorphic growth seen
in the testis (Schmahl et al.,
2000
). In addition, Sf1 acts on numerous target genes
(Val et al., 2003
) that are
expressed during gonadal development. Thus, the delay in Sertoli and Leydig
cell differentiation observed in the Sf1 heterozygous male gonad
might reflect reduced numbers of progenitor cells, impaired differentiation,
reduced transactivation of marker genes, or several of these mechanisms. A
gonad-specific knockout of Sf1 similarly failed to express
Cyp11a1 and Star at E14.5 and 16.5, which resulted in
hypoplastic testes and cryptorchidism
(Jeyasuria et al., 2004
).
Furthermore, the number of proliferating cells observed at E12.5 in the XY
gonad-specific Sf1 knockout was significantly lower than in wild
type. It is notable that humans with heterozygous SF1 mutations
exhibit a spectrum of adrenal insufficiency and gonadal dysgenesis, including
XY sex reversal (Jameson,
2004
; Ozisik et al.,
2003a
). Thus, the dose-dependent effects of SF1 are even
more pronounced in humans than in murine models.
The delay in Sertoli and Leydig cell function associated with Sf1
haploinsufficiency provides an opportunity to assess functional interactions
with Dax1. The consequences of Dax1 deficiency on testis
development have been documented previously
(Meeks et al., 2003a).
Although the loss of either Sf1 or Dax1 function alters
early testis development, their effects are distinct. Absence of Dax1
predominantly alters the differentiation of peritubular myoid cells, and the
patterning of fetal Leydig cells along the ventromedial to dorsolateral axis.
Sf1 regulates the temporal differentiation of Sertoli and Leydig
cells, and there is a predominant spatial dependence exhibited in the anterior
and posterior poles of the gonads. Sry expression begins in the
central region of the gonad and extends anteriorly, followed by completion at
the posterior end (Bullejos and Koopman,
2005
). It is possible that factors downstream of Sry
follow this spatiotemporal pattern.
Because the Dax1 promoter contains Sf1-regulatory elements
(Burris et al., 1995;
Hoyle et al., 2002
;
Kawabe et al., 1999
;
Yu et al., 1998a
), the defects
observed in the Sf1 heterozygote may be explained in part by reduced
Dax1 expression. Semi-quantitative RT-PCR analysis of urogenital
ridge tissue confirmed there was a decreased number of Dax1
transcripts in Sf1 heterozygous gonads at E11.5 by about 50% (data
not shown), consistent with previous reports
(Hoyle, 2002
). Nevertheless,
the phenotypic features of the Sf1 heterozygous gonad are more
pronounced than those seen in Dax1 null mutant, indicating distinct
functions.
Although in vitro studies of Dax1 inhibition of Sf1 transactivation provide
a relatively straightforward model for how these factors interact, the
distinct effects of individual Sf1 and Dax1 mutations
presage the consequences of the combined Sf1/Dax1 mutation. Indeed,
we found that testis development was affected to a greater degree in the
combined Sf1/Dax1 double mutant. In particular, the fetal Leydig cell
markers Cyp17 and Cyp11a1 were absent at E13.5. The fetal
Leydig cells ultimately recover in the Sf1/Dax1 mutant and their
population is normal by 2 weeks after birth, prior to the proliferation of
adult Leydig cells. Sertoli cells appear to have selective roles for
Sf1 and Dax1. Amh expression was reduced in the Sf1
heterozygote, consistent with the presence of Sf1-regulatory elements in this
gene (Hatano et al., 1994;
Shen et al., 1994
).
Unexpectedly, Dax1 null gonads have reduced Amh production
in vivo, although Dax1 has been shown to mediate repression at the
transcriptional level in vitro (Nachtigal
et al., 1998
). By E12.5, both of the single mutants recover
Amh expression, but recovery is more delayed in the double mutant. Of
note, adult Leydig cells are present in Sf1/Dax1 double mutant mice
and steroidogenesis is normal in the adult testis (data not shown). In spite
of delayed steroidogenic enzyme gene expression, testis descent and secondary
male reproductive features were unaffected in single and double mutants, and
there was no persistence of Müllerian ducts (data not shown).
The phenotype of the combined Sf1/Dax1 mutation is reminiscent of
the Dhh knockout, which also exhibits a delay in fetal Leydig cell
development and function (Yao et al.,
2002). Another feature of the Dhh knockout male gonad is
a defect in peritubular myoid cell development
(Clark et al., 2000
;
Pierucci-Alves et al., 2001
),
a feature also seen in the Dax1 null mutant
(Meeks et al., 2003a
).
Dhh is expressed by Sertoli cells and acts via the Ptc1 receptor on
fetal Leydig cells. At E11.5, Dhh expression was greatly reduced in
Sf1/Dax1 double mutant gonads but was partially recovered by E12.5.
Hence, a temporal delay in Dhh expression in Sf1/Dax1
mutants from E11.5 to E12.5 precedes the delay in fetal Leydig cell
differentiation from E13.5 to E14.5. In addition to Sf1 and Dax1,
Pdgfra also acts upstream of Dhh. Homozygous knockouts of
Pdgfra show delayed Dhh expression from 11.5 to 12.5, with a
concomitant decrease in Cyp11a1
(Brennan et al., 2003
).
The delay in Dhh and Amh expression suggests that
Sf1 and Dax1 converge on Sertoli cells to modulate key
molecular pathways in male differentiation. However, Sox9 expression
is relatively preserved, suggesting differential effects on specific genes.
The crucial genetic interaction of Sf1 and Dax1 appears to
occur early in the bipotential stage at 11.5 dpc or before. The precise
mechanism for this interaction is currently unknown. It remains plausible that
Dax1 exerts a repressive function for a subset of Sf1-regulated genes that
somehow regulate the timing of Sertoli cell differentiation, or Dhh
and Amh expression. Given the multiple functions of Sf1 in male gonad
development (coelomic epithelial proliferation, Amh production, and
steroidogenesis), Dax1 repression of Sf1 target genes might
be highly variable and depend on both the amount of Sf1 protein
present and the number of Sf1 DNA-binding elements on the target gene
promoter and (Hanley et al.,
2001). At present, the regulatory elements of the Dhh
promoter have not been characterized but may contain regulatory elements that
allow cooperative rather than antagonistic actions of Sf1 and
Dax1. Alternatively, Sf1 and Dax1 may act
indirectly to delay Dhh expression by altering cell lineage
restriction prior to Dhh expression. This could include paracrine
effects on Sertoli cells that express Dhh. The observation that
single mutations of Sf1 and Dax1 influence the spatial
expression of genes in the developing gonad is consistent with effects on
positional cues or cell-cell interactions.
In a previous study, we analyzed the effect of allelic loss of Sf1
on a Dax1 null background with respect to adrenal development and
function (Babu et al., 2002).
Double mutation of Sf1 and Dax1 restored adrenal weight and
corticosterone production. Allelic loss of Sf1 corrected the
overexpression of Cyp21 and the Acthr in the Dax1
null adrenal gland. These findings in the adrenal gland are reminiscent of the
selective repression of Cyp19 in adult Leydig cells of the testis
(Wang et al., 2001
). Taken
together, these studies of Sf1 and Dax1 interactions in vivo
suggest antagonistic interactions for some target genes, such as Cyp21,
Acthr and Cyp19. However, target genes, such as Dhh and
Amh, require cooperative functions of Sf1 and Dax1.
It is also likely that these nuclear factors function independently, as
evidenced by the distinct features found in single gene mutant phenotypes of
the adrenal gland and gonad. These discrete actions of Sf1 and
Dax1 are also consistent with the clinical consequences of human
SF1 and DAX1 mutations, each of which impair adrenal and
testis development but exhibit distinct histological characteristics.
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ACKNOWLEDGMENTS |
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