1 Division of Hematology and Oncology, Childrens Hospital and Dana Farber Cancer Institute, Department of Pediatric Oncology, and Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA
2 The Jackson Laboratory, Bar Harbor, ME, USA
3 The Ben May Institute for Cancer Research, University of Chicago, Chicago, IL, USA
* Present address: Department of Genetics, Dartmouth Medical School, Hanover, NH, USA
Author for correspondence (e-mail: stuart_orkin{at}dfci.harvard.edu)
Accepted 1 July 2002
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SUMMARY |
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Key words: Testis, GATA4, FOG2, Sry, Sertoli cell, Sex reversal, Mouse
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INTRODUCTION |
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The GATA zinc-finger transcription factors (designated GATA1 to GATA6) recognize the consensus target sequence (T/A)GATA(A/G) and play critical roles in various developmental processes, including hematopoietic and T cell differentiation, cardiac and coronary vasculature development, and liver, lung and gut morphogenesis (reviewed by Orkin, 2000; Molkentin, 2000
; Ho and Glimcher, 2002
; Van Esch et al., 2000
; Rossi et al., 2001
; Jacobsen et al., 2002
; Yang et al., 2002
). Although the precise roles GATA proteins play in gonadal development are not fully explored, two Gata genes are known to be expressed in fetal mouse gonads. Gata2 (GATA-binding protein 2) is expressed between E10.5-15.5 in XX gonads and XX and XY mesonephroi, but not in XY gonads. Gata2 is not expressed in XX gonads that lack germ cells, although mesonephric expression is maintained. At E13.5, Gata2 expression is restricted to germ cells in XX gonads (Siggers et al., 2002
), suggesting that it plays a role in ovarian germ cell development.
By contrast, Gata4 appears to be the sole GATA family member active in somatic (and not germ) cells of the genital ridge (Heikinheimo et al., 1997; Viger et al., 1998
). At E11.5, Gata4 is expressed in somatic cells of both XX and XY genital ridges (Heikinheimo et al., 1997
; Viger et al., 1998
; Ketola et al., 2000
). At E13.5, Gata4 expression becomes sexually dimorphic: in XY gonads expression is upregulated in Sertoli cells and downregulated in interstitial cells, whereas in XX gonads, expression is downregulated in all cells. Gata4 expression persists in the somatic cells of postnatal testes and is re-activated in adult ovaries with predominant expression in granulosa cells (Heikinheimo et al., 1997
; Viger et al., 1998
). GATA4 has been shown to bind to a consensus site in the Mis (Müllerian inhibiting substance, also known as anti-Müllerian homone, Amh) promoter and activate expression of a Mis reporter construct in vitro (Viger et al., 1998
). Because Gata4/ mice die at
E7.0-9.5 (Kuo et al., 1997
; Molkentin et al., 1997
) analysis of gonadal differentiation in the absence of GATA4 is not possible. Both Gata5 and Gata6 also are expressed throughout the mouse urogenital system, but only during the late fetal and postnatal stages (Morrisey et al., 1996
). In addition, Sertoli cells in the postnatal testis express Gata1, which represents the only reported extra-hematopoietic site of Gata1 expression (Yomogida et al., 1994
).
The normal in vivo function of GATA factors in vertebrates and Drosophila requires physical interaction with multitype zinc-finger proteins of the FOG (Friend of GATA) family (FOG1, FOG2, xFOG and USH) (for reviews, see Cantor and Orkin, 2001; Fossett and Schulz, 2001
). Previously, we and others reported expression of a FOG family member, Fog2 (friend of GATA2; Zfpm2 Mouse Genome Informatics), in the developing mouse gonad as early as E11.5 (Lu et al., 1999
; Svensson et al., 1999
; Tevosian et al., 1999
). Fog2 also is expressed in cardiac and nervous tissues and is strictly required for mouse cardiac development. Mouse fetuses homozygous for a null allele of Fog2 (Fog2/) die at mid-gestation from a cardiac defect characterized by a thin ventricular myocardium, common atrioventricular canal and the Tetralogy of Fallot malformation. Because Fog2/ embryos survive until
E14.5, analysis of early gonad development in the absence of FOG2 is possible. Partial rescue of cardiac function using a cardiac alpha myosin heavy chain (
MHC) driven Fog2 transgene specifically expressed in the myocardium, extends viability of Fog2/ fetuses to
E17.5 (Tevosian et al., 2000
), thus allowing examination of gonad development in the absence of Fog2 as late as E17.5. As noted above, Gata4/ embryos die at
E7.0-9.5, which precludes analysis of their gonadal differentiation. However, this problem is overcome by using a Gata4 knock-in allele (Gata4ki, a V217G amino acid substitution) that abrogates the interaction between GATA4 and FOG2 (or FOG1) (Crispino et al., 2001
). Homozygous Gata4ki embryos survive to E13.5 but then they die from cardiac abnormalities similar to those noted in Fog2/ embryos (Crispino et al., 2001
). Thus, the Gata4ki allele allows unique insight into the importance of the GATA4/FOG interaction in mammalian gonad development. We report that either abrogation of GATA4/FOG interaction or Fog2 loss result in the equivalent defect in mouse gonadal differentiation.
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MATERIALS AND METHODS |
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Whole-mount RNA in situ hybridization
All recombinant DNA work was accomplished using standard techniques. Probes provided by others are summarized in Table 1. Additional probes were generated according to Greco and Payne (Greco and Payne, 1994) from total testis RNA using a Superscript II RT-PCR kit according to the manufacturers instructions (Gibco). The genes together with primers used for RT-PCR are: P450scc (cholesterol side-chain cleavage) 5'-CTGAGTACTGGAAAGGGAGCTG-3' and 5'-TCACTGATGACCCCTGAGAAAT-3'; 3ßHSD (3ß-hydroxysteroid dehydrogenase/
5-
4-isomerase) 5'-TACATGGCTCTGGGAGTTATAAGGTCC-3' and 5'-GCTTCAGAAAGCAATGGGATTTTACC-3'; and P450c17 (17
-hydroxylase/ C17-20 lyase) 5'-GCCTGACAGACATTCTGATACAAGCC-3' and 5'-CCCTTCATTGCTGCCAAGTAGAAAAC-3'. PCRs were performed for 30 cycles (95°C for 1 minute, 55°C for 1 minute 30 seconds and 72°C for 3 minutes), and 1 cycle for 5 minutes at 72°C. PCR fragments were cloned using the TOPO-TA cloning kit (Invitrogen) and fully sequenced. Whole-mount in situ hybridization with riboprobes labeled with digoxigenin-UTP (Roche) was performed following standard procedures. Gonads were dissected from embryos that were fixed with 4% paraformaldehyde in 1xPBS and analyzed post hybridization with a Nikon Optiphot dissection microscope. Images were processed and assembled using Photoshop 5.5 (Adobe) and CorelDraw (Corel) software.
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Immunofluorescent histochemistry and confocal microscopy
Detailed methods for examining gonad morphology and marker protein expression have been described (Albrecht and Eicher, 2001). Briefly, tissue samples were fixed in 4% paraformaldehyde in PBS, rinsed twice in PBS and incubated for 24 hours in blocking buffer (1% BSA, 0.1% Saponin, 0.02% sodium azide in PBS). Samples were incubated in primary antibody diluted in fresh blocking buffer for 24 hours, washed extensively, incubated in fluorphore-conjugated secondary antibody diluted in fresh blocking buffer for 24 hours, and washed extensively. All samples were analyzed by three-color confocal microscopy (Leica TCS-NT) as whole-mounts in SlowFade-Light Antifade (Molecular Probes). Confocal images were assembled using MetaMorph (Universal Imaging) and Photoshop (Adobe). Pertinent information regarding the primary antibodies used is listed in Table 2. All secondary antibodies were used at 1:500 dilution and were from Jackson ImmunoResearch (Cy3 and Cy5 conjugated) or Molecular Probes (AlexaFluor 488).
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RESULTS |
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DISCUSSION |
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GATA4/FOG2 interaction is required for normal Sry expression
The differentiation of the genital ridge and induction of Sf1 and Wt1expression appears to be grossly normal in the absence of FOG2 or GATA4. Fog2/ XY gonads did initiate the male sex determination program by activating Sry expression, but Sry transcript levels were significantly reduced. Given that several inherited sex reversal conditions in mice are correlated with low Sry expression levels (Laval et al., 1995; Washburn et al., 2001
; Nagamine et al., 1999
; Hammes et al., 2001
), it is likely that lack of testicular tissue development in Fog2/ XY and Gata4ki/ki XY mice results from failure of Sertoli cell differentiation. The decrease in Sry transcript levels could be caused by a reduced number of Sry-expressing cells or a lower level of Sry expression per cell. Further experiments will distinguish between these possibilities. Whichever the case, Sry is a target of GATA4/FOG2 regulation, either directly or indirectly. It is possible that the GATA4/FOG2 complex interacts with the Sry promoter directly to activate its expression, or GATA4/FOG2 may participate in a parallel pathway. At E17.5 XY Fog2/ gonads are not simply sex-reversed gonads because they do not resemble normal ovaries. Hence, Sry is unlikely to be the sole target of GATA4/FOG2 regulation and the data strongly indicates that GATA4/FOG2 regulation is needed for normal ovarian development as well. At this time the paucity of molecular markers expressed early in ovarian determination makes it more difficult to determine what affect the absence of FOG2 or GATA4 has on ovarian development. However, when early ovarian markers become available, the role of FOG2 and GATA4 in ovarian development can be explored more fully.
GATA4/FOG2 are likely to carry multiple functions during gonadal development
Whether GATA4 and FOG2 have in vivo roles in testis determination downstream of Sry cannot be readily assessed given that Sry expression was insufficient to initiate Sertoli cell differentiation, thus causing testis differentiation to be blocked early. For example, Fog2/ XY gonads fail to properly downregulate Wnt4 expression and activate steroidogenesis. However, because an early defect in the differentiation of pre-Sertoli cells prevents further testis differentiation, it is not yet possible to determine if FOG2 or GATA4 act cell-autonomously later in Leydig cells or if they participate in subsequent events in gonadal development and/or spermatogenesis. Also, given the decisive role FOG2 and GATA4 play in the transformation of migrating epicardial cells during cardiac development and formation of coronary vasculature (Tevosian et al., 2000; Crispino et al., 2001
), it is possible that these proteins are involved in the migration of mesonephric cells into developing XY gonads. Conditional knockouts of Fog2 and Gata4 and other transgenic approaches will allow the dissection of the multiple roles these transcriptional regulators play in the development of various cell lineages in the gonads of both sexes.
In summary, our results provide a basis for incorporating the GATA/FOG paradigm into the genetic pathway of sex determination and sexual differentiation.
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ACKNOWLEDGMENTS |
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