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RESEARCH |
Graduate School of Science and Technology, Kobe University, Kobe 657-8501, Japan and 1 Graduate School of Biostudies, Kyoto University, Kyoto 606-8507, Japan
Correspondence should be addressed to M Moniruzzaman; Email: 026d910n{at}stu.kobe-u.ac.jp
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Abstract |
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Introduction |
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Several growth factors and cytokines are thought to regulate the process of germ cell/oocyte survival and follicular development (Reynaud & Driancourt 2000, Eppig 2001). Among those KIT, a tyrosine kinase receptor and its ligand, KIT Ligand (KL, which is also known as steel factor, stem cell factor, or mast cell growth factor) are important regulators for the survival of germ cells, growth of oocytes, and folliculogenesis (Driancourt et al. 2000). mRNA for both soluble and membrane-bound forms of KL was detected in juvenile and adult mouse ovaries (Manova et al. 1993) and in granulosa cells isolated from mouse preantral follicles (Joyce et al. 1999). Expression of KIT mRNA and KIT protein has been detected in primordial, growing and fully grown oocytes (Manova et al. 1993).
KIT and KL are encoded at white spotting (W) and steel (Sl) loci in the mouse respectively (Geissler et al. 1988, Chabot et al. 1988, Copeland et al. 1990, Huang et al. 1990, Zsebo et al. 1990). Mutant mice for the W and Sl loci show similar phenotypes such as anemia, a decreased number of mast cells, lack of pigmentation, and infertility (Russell 1979). Many alleles of variable severity at both W and Sl loci have been identified (Besmer et al. 1993). Wv mutant mice with the C57BL/6 background have a single-point mutation at 2007 (C–T) of the kit sequence, which involves the change of threonine to methionine at position 660 in the cytoplasmic region of KIT. In Wv/Wv mice, oogenesis completely fails, resulting in no follicles or oocytes in the ovaries. Moreover, KIT/KL is known to play a key role in activation of primordial follicles, oocyte growth and then follicular development (Driancourt et al. 2000). It is reported that neutralizing KIT by injecting ACK2, a function-blocking antibody, causes disturbances in initial follicle recruitment in mice (Yoshida et al. 1997). Oocyte growth and follicle development stopped at the primary stage in KL mutant mice (Kuroda et al. 1988, Huang et al. 1993). Furthermore, results from in vitro studies suggest that KL promotes the development of primordial follicles in rodents (Parrott & Skinner 1999). Packer et al.(1994) have reported that KIT and KL are required for oocyte growth. Inhibition of oocyte growth was obtained as a result of ACK2 treatment in vitro.
Fas is a member of death receptor family. It induces programmed cell death in various organs including testis and ovary. It is expressed in granulosa cells and oocytes during folliculogenesis, and in luteal cells (Sakamaki et al. 1997). Its expression in granulosa and luteal cells suggests that Fas is involved in follicular atresia and luteolysis. Defective KIT signaling leads to the activation of a Fas-mediated apoptotic signal in germ cells, and thus Fas is involved in germ cell loss in KIT-deficient Wv/Wv mice (Sakata et al. 2003). Since the rescue of testicular germ cells as well as oocytes by Fas deficiency in KIT-deficient mice has been revealed, the role of KIT in oocyte growth and follicular development has become an issue to be reconsidered.
The present study was aimed at further elucidating the involvement of KIT in the survival of female germ cells, the activation of primordial oocytes, and follicular development. We examined ovaries from Wv/Wv:Fas+/+, Wv/Wv:Fas–/– and +/+:Fas–/– mice in comparison with those from wild-type +/+:Fas+/+ mice. Soon after gonadal differentiation at 13 dpc, the numbers of oogonia were examined. The formation of primordial follicles and initiation of oocyte growth were examined in ovaries of 2-day old mice. Follicular development and oocyte growth were examined in the ovaries of 14-day old mice. The ovaries from fetal (13 dpc) and neonatal (2-day old) mice were transplanted to immuno deficient mice to study oocyte growth and follicular development under the condition of being isolated from any extraovarian effects of KIT- and Fas-deficiency.
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Materials and Methods |
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This study was approved by the Institutional Animal Care and Use Committee (Permission number: 16-08-01) and carried out according to the Guidelines of Animal Experimentation of Kobe University, Japan.
Genotyping
The KIT-deficient genotype was distinguished by their coat color. The homozygous KIT-deficient mice were identified by their white coat color, while the heterozygous mice had a black coat with white spots on the neck, back and/or abdomen regions (Fig. 1A
). This coat color first appeared at around 2 days after birth. To detect the genotype of the fetuses, small pieces of skins were transplanted under the kidney capsules of SCID mice. After 3 weeks, kidneys were collected and the color of the transplanted skins were examined. White skins corresponded to the homozygous KIT-deficient genotype, Wv/Wv, and black corresponded to +/+ or Wv/+ (Fig. 1B and C).
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Transplantation
The sex of fetal gonads at 13 dpc was identified by the testis cords observed in male gonads. Ovaries were collected from +/+:Fas+/+(or Wv/–:Fas+/+; n=4 and 4),+/+:Fas–/– (n=4 and 4), Wv/Wv:Fas+/+ (n=3 and 3) and Wv/Wv:Fas–/–(n=3 and 3) mice at 13 dpc and at 2 days respectively. From each mouse, one ovary was transplanted and the other was fixed for histological examination. At 14 days, ovaries were collected from +/+:Fas+/+(n=4),+/+:Fas–/–(n=4), Wv/Wv:Fas+/+ (n=4) and Wv/Wv:Fas–/– (n=4) mice. From each mouse, one ovary was taken for histological examination. For transplantation, SCID mice were anesthetized by i.p. injection of sodium pentobarbital (Nembutal; Dainippon Pharmaceutical Co. Ltd, Osaka, Japan), and the left kidney was exteriorized. A small hole was torn in the kidney capsule using fine forceps, and one ovary was inserted underneath the capsule of each SCID mouse. The transplantation procedure was performed at room temperature and the mice were kept on a warming plate (37 °C) for 24 h.
Twenty-one and twelve days after transplantations of fetal and neonatal ovaries (corresponding to the ovaries of a 14-day old) respectively, the kidneys containing transplanted ovaries were collected and washed with PBS prior to histological examination.
Histological examinations
Ovaries and ovarian transplants were fixed in 3% paraformaldehyde in PBS. They were dehydrated, embedded in methacrylate resin (JB-4; Polyscience Inc., Niles, IL, USA), serially sectioned by 5 µm, and stained with hematoxylin and eosin. In the fetal ovaries, germ cells were distinguished from somatic cells based on differences in their cellular size (germ cells being much larger than somatic cells) and morphology (germ cells and their nuclei are spherical). The number of germ cells, oocytes, and follicles at various stages were recorded. Follicles were counted in the sections where the oocyte nucleus was seen. To count the number of germ cells, their nuclei were counted in every section. Although the nuclei of germ cells were around 5 µm, most of the nuclei found in a section were not visible in adjacent sections. However, germ cells and follicles were observed carefully to avoid the double counting in adjacent sections. Follicles were classified according to the number and morphology of granulosa cell layers: primordial follicles with one layer of flattened granulosa cells surrounding the oocyte, primary follicles with a single layer of cuboidal granulosa cells, secondary follicles with two or more layers of granulosa cells but no antrum, and antral follicles having at least an antral cavity with multiple layers of granulosa cells. The diameter of each oocyte (excluding the zona pellucida) was measured by taking the average of two perpendicular measurements of the maximum-diameter section with an ocular micrometer (Nikon, Tokyo, Japan).
Statistical analysis
Data are presented as the means±S.E.M. They were subjected to one-way ANOVA, and the significance of differences among means was determined by Tukey’s multiple range test. Differences at P<0.05 were considered statistically significant.
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Results |
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and 4). The number of oocytes decreased to 2363±126 (n=4) at 2 days after birth (Figs 3 and 4). Higher numbers of germ cells were found in fetal and postnatal ovaries of +/+:Fas–/–(or Wv/+:Fas–/–) mice than in those of +/+:Fas+/+ (or Wv/+:Fas+/+) mice (Fig. 4). Ovaries from KIT-deficient mice (Wv/Wv:Fas+/+ and Wv/Wv:Fas–/–) were smaller than those from age-matched other genotypes at every stage (Figs 2 and 3). Wv/Wv:Fas+/+ovaries at 13 dpc contained 1106±72 (n=3) germ cells. Their ovaries contained no oocytes at 2 or 14 days of age (Figs 3 and 4). On the other hand, a higher number of germ cells (3843±108; n=3) was observed in the Wv/Wv:Fas–/–genotypes than in Wv/Wv:Fas+/+at 13 dpc. Wv/Wv:Fas–/– mice contained 528±91 (n=3) oocytes at 2 days of age, but the number decreased to 54 ±2 (n=4) at 14 days.
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and Table 1). In 14-day old, some follicles had developed to the antral stage. In 2-day old Wv/ Wv:Fas–/– mice, few follicles developed to the primary stage, while most follicles remained at the primordial stage. In 14-day old, 15±1% (n=4) follicles had developed to the secondary stage, and small proportions (3±0%; n=4) developed to the antral stage. Table 2 shows the oocyte growth in these mice. In 2-day old +/+:Fas+/+ and +/+:Fas–/– mice, ovaries contained mainly non-growing oocytes. In 14-day old, some oocytes had grown to more than 50 µm. Similarly, in Wv/Wv:Fas–/– mice, a proportion of oocytes had grown larger than 20 µm in diameter at 2 days of age, and growing oocytes of various sizes were observed at 14 days, although the number was significantly lower than those in the other two types of mice.
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Oocyte growth in the transplanted ovaries
In transplanted fetal and neonatal ovaries, oocytes grew and follicles developed (Figs 5 and 6). Twenty-one days after transplantation, fetal ovaries from +/+:Fas+/+and +/+:Fas–/– mice contained 1561±64 (n=4) and 2109±34 (n=4) oocytes respectively (Fig. 4). Similar numbers of oocytes were obtained at 12 days after transplantation of neonatal ovaries from the same genotypes. No oocytes or germ cells were found after transplantation of fetal and neonatal ovaries from Wv/ Wv:Fas+/+ mice. On the other hand, 384±66 (n=3) and 276±22 (n=3) oocytes were obtained after transplantation of fetal and neonatal ovaries from Wv/ Wv:Fas–/–mice respectively. The numbers of oocytes in transplants were higher than those in the ovaries of 14-day old in Wv/Wv:Fas–/– mice. The loss of oocytes was significantly reduced in transplanted ovaries.
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and Table 1). Follicular development was also observed in neonatal ovaries after transplantation (Fig. 6). Similarly, after transplantation offetal and neonatal ovaries from Wv/Wv:Fas–/– mice, follicles developed up to the antral stage. The numbers of primary and secondary follicles obtained in the transplanted ovaries were higher than those in the ovaries from 14-day old Wv/Wv:Fas–/– mice (Table 1). After transplantation of fetal ovaries from +/+:Fas+/+and +/+:Fas–/–mice, some oocytes grew to more than 50 µm in diameter (Table 2). Similarly, growing oocytes were also found in transplanted neonatal ovaries. The numbers of growing oocytes obtained in transplanted ovaries were significantly higher than those in the ovaries of 14-day old Wv/Wv:Fas–/–mice. These results showed that no germ cells/oocytes survived in the transplanted fetal ovaries from Wv/Wv:Fas+/+ mice, while oocytes were able to grow with follicular development in the transplanted ovaries from Wv/Wv:Fas–/– mice.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionAcknowledgementsReferences |
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The numbers of oocytes found in 2-day old +/+ :Fas–/– and +/+:Fas+/+ mice were lower than their germ cell populations at 13 dpc. The neonatal +/+ :Fas–/– mice possessed higher numbers of oocytes than +/+:Fas+/+ mice. This might be caused by the lower rate of germ cell/oocyte death induced by Fas (Sakata et al. 2003). KIT-deficient Wv/Wv:Fas+/+ mouse ovaries contained no oocytes after birth, as reported previously (Russell 1979, Besmer et al. 1993). This suggests that KIT is involved in the survival of germ cells/oocytes in mice. Inhibition of KIT promotes the death of oocytes in vitro (Reynaud et al. 2000). Fas-deficiency rescued the oocytes in neonatal Wv/ Wv:Fas–/– mice. However, the numbers of germ cells/ oocytes in fetal and neonatal ovaries were lower in Wv/Wv:Fas–/– than in +/+:Fas+/+ mice. Moreover, a lot of germ cells/oocytes died in Wv/Wv:Fas–/– mice, especially in the postnatal period. This is thought to be due to a partial or an incomplete rescue by Fas-deficiency. Some apoptotic factors other than Fas may be involved in the death process of germ cells/oocytes in Fas-knockout mice. It has been reported that a deficiency of p53, a tumor suppressor protein, which is known to cause apoptosis, rescues the germ cells in Wv/Wv mice (Jordan et al. 1999).
Wv/Wv:Fas+/+ and Wv/Wv:Fas–/– mice displayed white coat color and poor body conditions. They often died within 2 weeks. To overcome these adverse conditions, their ovaries at the fetal and neonatal stages were transplanted in SCID mice. No oocytes survived in the transplanted ovaries from fetal Wv/Wv:Fas+/+ mice. This indicates that the survival of germ cells in transplants depends on the genotype of the ovaries. After transplantation of neonatal ovaries from Wv/Wv:Fas+/+ mice, oocytes were not generated or supplied from an extragonadal source, as reported by Johnson et al.(2005). They have postulated that new oocytes are generated from germ line stem cells migrating from bone marrow through the blood stream.
The mechanisms concerning the entrance of primordial oocytes into the growth phase remain largely a mystery, with KIT–KL interaction being known to play a pivotal role in this process in rodents. It has been demonstrated that KL promotes the development of primordial follicles in rodent ovaries in vitro (Packer et al. 1994, Parrott & Skinner 1999). KL mutant Sl/Slt and Slpan/ Slpan females are sterile, as their follicular development is arrested at the primary stage and oocytes do not grow more than 20 µm (Kuroda et al. 1988, Huang et al. 1993). The inhibiting role of KIT has been shown by experiments using its specific antibody, ACK2. The numbers of growing oocytes decreased in ACK2-treated rodent ovaries (Packer et al. 1994, Parrott & Skinner 1999). Yoshida et al.(1997) injected mice with ACK2 at various times during the first 2 weeks after birth and reported that neutralization of KIT caused disturbances in initial follicle recruitment. However, no direct evidence of the involvement of KIT in oocyte growth has been obtained in KIT mutant mice, because KIT mutation causes severe death of germ cells during the prenatal stage, and therefore, no oocytes survive after birth (Russell 1979, Besmer et al. 1993). The present study shows that oocytes are able to grow with follicular development in KIT-deficient Wv/Wv:Fas–/– mice.
Fas might not be associated with oocyte growth or follicular development in mice, because in the +/+ :Fas–/–genotypes, oocytes grew and follicles developed as in +/+:Fas+/+. However, Fas-mediated apoptotic signals crosstalk with KIT-mediated survival signals in the mouse gonads. Sakata et al.(2003) detected Fas transcripts in the testis of KIT-deficient mice but not in that of wild-types. They have revealed that KIT inhibits Fas-mediated apoptosis through the PI3K (phosphatidyl-inositol 3-kinase) -AKT (also referred to as protein kinase B) pathway. Blocking of KIT signals by ACK2 causes germ cell degeneration in wild-type, but not in Fas-deficient mice. This indicates that Fas is involved in germ cell degeneration in the absence of KIT signaling. In the absence of both KIT and Fas, the germ cells are rescued. In such a condition, surviving oocytes are able to grow with follicular development. In summary, our results show that oocytes grow and follicles develop without KIT signaling, although KIT might be essential for survival of germ cells/oocytes in mice.
Factors including KL, GDF-9, EGF and leukemia inhibitory factor (LIF) are known to be involved in oocyte growth and follicular development (Eppig 2001, Skinner 2005). It is not clear which factor(s) promotes the processes of oocyte growth and follicular development in a KIT-deficient condition. A recent report suggests that the defects of hematopoietic stem cells induced by KIT-deficiency are able to overcome by transgenic expression of erythropoietin (Waskow et al. 2004), whose receptor associates with PI3K (Damen et al. 1993). PI3K (Liu 2006) and AKT (Reddy et al. 2005) are thought to be downstream effectors of KIT, and they mediate oocyte growth. It has not been known whether these intracellular effectors are activated by other cytokines or growth factors to compensate the KIT signaling for oocyte growth and follicular development in a KIT-deficient condition. In this regard, further study is necessary to understand the mechanism involved in oocyte growth and follicular development.
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Acknowledgements |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionAcknowledgementsReferences |
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Footnotes |
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionAcknowledgementsReferences |
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