scholarly journals BCL2-modifying factor promotes germ cell loss during murine oogenesis

Reproduction ◽  
2016 ◽  
Vol 151 (5) ◽  
pp. 553-562 ◽  
Author(s):  
Kavitha Vaithiyanathan ◽  
Seng H Liew ◽  
Nadeen Zerafa ◽  
Thilini Gamage ◽  
Michele Cook ◽  
...  
Keyword(s):  
Germ Cell ◽  
Germ Cells ◽  
Germ Line ◽  
Cell Loss ◽  
Regulatory Proteins ◽  
Primordial Follicles ◽  
Large Numbers ◽  
Female Germ Line ◽  
Low Levels

Abstract Apoptosis plays a prominent role during ovarian development by eliminating large numbers of germ cells from the female germ line. However, the precise mechanisms and regulatory proteins involved in germ cell death are yet to be determined. In this study, we characterised the role of the pro-apoptotic BH3-only protein, BCL2-modifying factor (BMF), in germ cell apoptosis in embryonic and neonatal mouse ovaries. BMF protein was immunohistochemically localised to germ cells at embryonic days 15.5 (E15.5) and E17.5 and postnatal day 1 (PN1), coincident with entry into the meiotic prophase, but was undetectable at E13.5, and only present at low levels at PN3 and PN5. Consistent with this expression pattern, loss of BMF in female mice was associated with a decrease in apoptosis at E15.5 and E17.5. Furthermore, increased numbers of germ cells were found in ovaries from Bmf−/− mice compared with WT animals at E15.5 and PN1. However, germ cell numbers were comparable between Bmf−/− and WT ovaries at PN3, PN5 and PN10. Collectively, these data indicate that BMF mediates foetal oocyte loss and its action limits the maximal number of germ cells attained in the developing ovary, but does not influence the number of primordial follicles initially established in ovarian reserve.

scholarly journals PUMA regulates germ cell loss and primordial follicle endowment in mice

Reproduction ◽  
2014 ◽  
Vol 148 (2) ◽  
pp. 211-219 ◽  
Author(s):  
Michelle Myers ◽  
F Hamish Morgan ◽  
Seng H Liew ◽  
Nadeen Zerafa ◽  
Thilini Upeksha Gamage ◽  
...  
Keyword(s):  
Cell Death ◽  
Germ Cell ◽  
Germ Cells ◽  
Ovarian Development ◽  
Fold Increase ◽  
Cell Loss ◽  
Postnatal Life ◽  
Critical Determinant ◽  
Primordial Follicles ◽  
Female Mice

The number of primordial follicles initially established within the ovary is influenced by the extent of germ cell death during foetal ovarian development, but the mechanisms that mediate this death have not been fully uncovered. In this study, we identified BBC3 (PUMA) (p53 upregulated modulator of apoptosis, also known as BCL2-binding component 3), a pro-apoptotic BH3-only protein belonging to the BCL2 family, as a critical determinant of the number of germ cells during ovarian development. Targeted disruption of the Bbc3 gene revealed a significant increase in the number of germ cells as early as embryonic day 13.5. The number of germ cells remained elevated in Bbc3−/− female mice compared with WT female mice throughout the remainder of embryonic and early postnatal life, resulting in a 1.9-fold increase in the number of primordial follicles in the ovary on postnatal day 10. The increase in the number of germ cells observed in the ovaries of Bbc3−/− mice could not be attributed to the altered proliferative activity of germ cells within the ovaries. Furthermore, BBC3 was found to be not required for the massive germ cell loss that occurs during germ cell nest breakdown. Our data indicate that BBC3 is a critical regulator of germ cell death that acts during the migratory phase of oogenesis or very soon after the arrival of germ cells in the gonad and that BBC3-mediated cell death limits the number of primordial follicles established in the initial ovarian reserve.

scholarly journals Quantification of healthy and atretic germ cells and follicles in the developing and post-natal ovary of the South American plains vizcacha, Lagostomus maximus: evidence of continuous rise of the germinal reserve

Reproduction ◽  
2014 ◽  
Vol 147 (2) ◽  
pp. 199-209 ◽  
Author(s):  
P I F Inserra ◽  
N P Leopardo ◽  
M A Willis ◽  
A L Freysselinard ◽  
A D Vitullo
Keyword(s):  
Germ Cell ◽  
Germ Cells ◽  
Germ Line ◽  
Cell Number ◽  
South American ◽  
The South ◽  
Foetal Life ◽  
Female Germ Line ◽  
Lagostomus Maximus ◽  
Mitotic Proliferation

The female germ line in mammals is subjected to massive cell death that eliminates 60–85% of the germinal reserve by birth and continues from birth to adulthood until the exhaustion of the germinal pool. Germ cell demise occurs mainly through apoptosis by means of a biased expression in favour of pro-apoptotic members of theBCL2gene family. By contrast, the South American plains vizcacha,Lagostomus maximus, exhibits sustained expression of the anti-apoptoticBCL2gene throughout gestation and a low incidence of germ cell apoptosis. This led to the proposal that, in the absence of death mechanisms other than apoptosis, the female germ line should increase continuously from foetal life until after birth. In this study, we quantified all healthy germ cells and follicles in the ovaries ofL. maximusfrom early foetal life to day 60 after birth using unbiased stereological methods and detected apoptosis by labelling with TUNEL assay. The healthy germ cell population increased continuously from early-developing ovary reaching a 50 times higher population number by the end of gestation. TUNEL-positive germ cells were <0.5% of the germ cell number, except at mid-gestation (3.62%). Mitotic proliferation, entrance into prophase I stage and primordial follicle formation occurred as overlapping processes from early pregnancy to birth. Germ cell number remained constant in early post-natal life, but a remnant population of non-follicular VASA- and PCNA-positive germ cells still persisted at post-natal day 60.L. maximusis the first mammal so far described in which female germ line develops in the absence of constitutive massive germ cell elimination.Free Spanish abstractSpanish translation of this abstract is freely available athttp://www.reproduction-online.org/content/147/2/199/suppl/DC1

GATA-like protein-1 (GLP-1) is required for normal germ cell development during embryonic oogenesis

Reproduction ◽  
2011 ◽  
Vol 141 (2) ◽  
pp. 173-181 ◽  
Author(s):  
Tamara J Strauss ◽  
Diego H Castrillon ◽  
Stephen R Hammes
Keyword(s):  
Germ Cell ◽  
Germ Cells ◽  
Germ Line ◽  
Primordial Follicle ◽  
Cell Loss ◽  
Basement Membranes ◽  
Cell Protein ◽  
Null Mouse ◽  
Cell Functions ◽  
Expression Of Genes

Oogenesis and primordial follicle formation are tightly linked processes, requiring organized and precisely timed communication between somatic and germ cells. Deviations in ovarian cell cross talk, or aberrant gene expression within one of the cell populations, can lead to follicle loss or dysfunction, resulting in infertility. Expression of GATA-like protein-1 (GLP-1) in ovarian somatic cells is required for normal fertility in female mice, as GLP-1 deficiency leads to the absence of oocytes at birth. However, the timing and nature of this germ cell loss is not well understood. In this study, we characterize the embryonic germ cell loss in GLP-1 null mice. Quantitative PCR demonstrates that ovarian Glp-1 mRNA is expressed in a bimodal pattern during embryogenesis, peaking at E13.5–14.5 and again at birth. In contrast, adult ovaries express low but detectable levels of Glp-1 mRNA. Analysis of developing GLP-1 null mouse ovaries shows that germ cells are appropriately specified and migrate normally to nascent gonads. Upon arrival at the gonad, precocious loss of germ cells begins at around E13.5. This loss is completed by birth and is accompanied by defects in the expression of genes associated with meiotic entry. Interestingly, somatic pregranulosa cells still form basement membranes surrounding germ line cysts and express mRNA encoding paracrine signaling molecules that communicate with oocytes, albeit at lower levels than normal. Together, these data imply that the somatic cell protein GLP-1 is not necessary for many pregranulosa cell functions but is required for germ cell survival.

scholarly journals VIABILITY OF FEMALE GERM-LINE CELLS HOMOZYGOUS FOR ZYGOTIC LETHALS IN DROSOPHILA MELANOGASTER

Genetics ◽  
1983 ◽  
Vol 103 (2) ◽  
pp. 235-247
Author(s):  
Antonio Garcia-Bellido ◽  
Leonard G Robbins
Keyword(s):  
Germ Cell ◽  
Germ Cells ◽  
Germ Line ◽  
Epidermal Cells ◽  
Chromosome Band ◽  
X Chromosomes ◽  
Different Types ◽  
Complementation Groups ◽  
Female Germ Line ◽  
Embryonic Arrest

ABSTRACT We have analyzed the viability of different types of X chromosomes in homozygous clones of female germ cells. The chromosomes carried viable mutations, single-cistron zygotic-lethal and semi-lethal mutations, or small (about six chromosome band) deletions. Homozygous germ-line clones were produced by recombination in females heterozygous for an X-linked, dominant, agametic female sterile. All the zygotic-viable mutants are also viable in germ cells. Of 16 deletions tested (uncovering a total of 93 bands) only 2 (of 4 and 5 bands) are germ-cell viable. Mutations in 15 lethal complementation groups in the zeste-white region were tested. When known, the most extreme alleles at each locus were tested. Only in five loci (33%) were the mutants viable in the germ line. Similar studies of the same deletions and point-mutant lethals in epidermal cells show that 42% of the bands and 77% of the lethal alleles are viable. Thus, germ-line cells have more stringent cell-autonomous genetic requirements than do epidermal cells. The eggs recovered from clones of three of the germ-cell viable zw mutations gave embryos arrested early in embryogenesis, although genotypically identical embryos derived from heterozygous oogonia die as larvae or even hatch as adult escapers. For two genes, homozygosis of the mutations tested also caused embryonic arrest of heterozygous female embryos, and in one case, the eggs did not develop at all. Germ-line clones of one quite leaky mutation gave eggs that were indistinguishable from normal. The abundance of genes whose products are required for oogenesis, whose products are required in the oocyte, and whose activity is required during zygotic development is discussed.

scholarly journals Germ cell loss is associated with fading Lin28a expression in a mouse model for Klinefelter's syndrome

Reproduction ◽  
2014 ◽  
Vol 147 (3) ◽  
pp. 253-264 ◽  
Author(s):  
Steffi Werler ◽  
Hannah Demond ◽  
Oliver S Damm ◽  
Jens Ehmcke ◽  
Ralf Middendorff ◽  
...  
Keyword(s):  
Mouse Model ◽  
Germ Cell ◽  
Germ Cells ◽  
Germ Line ◽  
Cell Loss ◽  
Klinefelter’S Syndrome ◽  
Klinefelter's Syndrome ◽  
Proliferating Cells ◽  
Underlying Causes ◽  
Marker Expression

Klinefelter's syndrome is a male sex-chromosomal disorder (47,XXY), causing hypogonadism, cognitive and metabolic deficits. The majority of patients are infertile due to complete germ cell loss after puberty. As the depletion occurs during development, the possibilities to study the underlying causes in humans are limited. In this study, we used the 41,XXY* mouse model to characterise the germ line postnatally. We examined marker expression of testicular cells focusing on the spermatogonial stem cells (SSCs) and found that the number of germ cells was approximately reduced fivefold at day 1pp in the 41,XXY* mice, indicating the loss to start prenatally. Concurrently, immunohistochemical SSC markers LIN28A and PGP9.5 also showed decreased expression on day 1pp in the 41,XXY* mice (48.5 and 38.9% of all germ cells were positive), which dropped to 7.8 and 7.3% on 3dpp, and were no longer detectable on days 5 and 10pp respectively. The differences in PCNA-positive proliferating cells in XY* and XXY* mice dramatically increased towards day 10pp. The mRNA expression of the germ cell markers Lin28a (Lin28), Pou5f1 (Oct4), Utf1, Ddx4 (Vasa), Dazl, and Fapb1 (Sycp3) was reduced and the Lin28a regulating miRNAs were deregulated in the 41,XXY* mice. We suggest a model for the course of germ cell loss starting during the intrauterine period. Neonatally, SSC marker expression by the already lowered number of spermatogonia is reduced and continues fading during the first postnatal week, indicating the surviving cells of the SSC population to be disturbed in their stem cell characteristics. Subsequently, the entire germ line is then generally lost when entering meiosis.

zfh-1 is required for germ cell migration and gonadal mesoderm development in Drosophila

Development ◽  
1998 ◽  
Vol 125 (4) ◽  
pp. 655-666 ◽  
Author(s):  
H.T. Broihier ◽  
L.A. Moore ◽  
M. Van Doren ◽  
S. Newman ◽  
R. Lehmann
Keyword(s):  
Cell Migration ◽  
Germ Cell ◽  
Germ Cells ◽  
Ectopic Expression ◽  
Homeodomain Protein ◽  
Mesoderm Development ◽  
Visceral Mesoderm ◽  
Temporal Course ◽  
Germ Cell Migration

In Drosophila as well as many vertebrate systems, germ cells form extraembryonically and migrate into the embryo before navigating toward gonadal mesodermal cells. How the gonadal mesoderm attracts migratory germ cells is not understood in any system. We have taken a genetic approach to identify genes required for germ cell migration in Drosophila. Here we describe the role of zfh-1 in germ cell migration to the gonadal mesoderm. In zfh-1 mutant embryos, the initial association of germ cells and gonadal mesoderm is blocked. Loss of zfh-1 activity disrupts the development of two distinct mesodermal populations: the caudal visceral mesoderm and the gonadal mesoderm. We demonstrate that the caudal visceral mesoderm facilitates the migration of germ cells from the endoderm to the mesoderm. Zfh-1 is also expressed in the gonadal mesoderm throughout the development of this tissue. Ectopic expression of Zfh-1 is sufficient to induce additional gonadal mesodermal cells and to alter the temporal course of gene expression within these cells. Finally, through analysis of a tinman zfh-1 double mutant, we show that zfh-1 acts in conjunction with tinman, another homeodomain protein, in the specification of lateral mesodermal derivatives, including the gonadal mesoderm.

Dual role of Ovol2 on the germ cell lineage segregation during gastrulation in mouse embryogenesis

Development ◽  
2022 ◽  
Author(s):  
Yuki Naitou ◽  
Go Nagamatsu ◽  
Nobuhiko Hamazaki ◽  
Kenjiro Shirane ◽  
Masafumi Hayashi ◽  
...  
Keyword(s):  
Germ Cells ◽  
Splice Variant ◽  
Epithelial To Mesenchymal Transition ◽  
Functional Relationship ◽  
Germ Line ◽  
Primordial Germ Cells ◽  
Cell Lineage ◽  
Animal Kingdom ◽  
Mesenchymal Transition

In mammals, primordial germ cells (PGCs), the origin of the germ line, are specified from the epiblast at the posterior region where gastrulation simultaneously occurs, yet the functional relationship between PGC specification and gastrulation remains unclear. Here, we show that Ovol2, a transcription factor conserved across the animal kingdom, balances these major developmental processes by repressing the epithelial-to-mesenchymal transition (EMT) driving gastrulation and the upregulation of genes associated with PGC specification. Ovol2a, a splice variant encoding a repressor domain, directly regulates EMT-related genes and consequently induces re-acquisition of potential pluripotency during PGC specification, whereas Ovol2b, another splice variant missing the repressor domain, directly upregulates genes associated with PGC specification. Taken together, these results elucidate the molecular mechanism underlying allocation of the germ line among epiblast cells differentiating into somatic cells through gastrulation.

Induction of cell—cell adhesion by monovalent antibodies in a germ cell culture

Development ◽  
1985 ◽  
Vol 90 (1) ◽  
pp. 211-222
Author(s):  
Wai Chang Ho ◽  
Kathleen B. Bechtol
Keyword(s):  
Monoclonal Antibodies ◽  
Cell Adhesion ◽  
Germ Cell ◽  
Germ Cells ◽  
Antigen Expression ◽  
Fab Fragment ◽  
Cell Age ◽  
Dose Dependent Fashion ◽  
Dose Dependent

Four monoclonal antibodies, XT-I, MT-23, MT-24 and MT-29, that bind the XT-1-differentiation-antigen of male germ cells have been used to investigate the biological role of the XT-1-molecule of germ cells in short-term primary culture. Cultures from 10 days postpartum mice demonstrate increasing numbers of antigen-positive germ cells and increased antigen expression per cell with succeeding days of culture. Treatment of the antigen-positive cultures with three of the monoclonal antibodies, XT-I, MT-23 and MT-24, increases germ cell-germ cell adhesion in a dose-dependent fashion. Treatment with the fourth monoclonal antibody, MT-29, does not induce cell adhesion. The monovalent, Fab fragment of XT-I-antibody also elicits tight cell adhesion, thus ruling out antibody cross linking of molecules or cells. Saturating or near saturating amounts of the positive antibodies are required to produce adhesion, a result consistent with perturbation of a function that is performed by the sum of action of many of the XT-1-molecules on the cell. The ability of germ cells to undergo antibody-elicited tight adhesion is dependent on germ cell age and/or XT-1-antigen concentration. We hypothesize that the XT- 1-molecule is involved in regulation of cell adhesion, an event which must occur in normal development.

scholarly journals Follistatin Regulates Germ Cell Nest Breakdown and Primordial Follicle Formation

Endocrinology ◽  
2010 ◽  
Vol 152 (2) ◽  
pp. 697-706 ◽  
Author(s):  
Fuminori Kimura ◽  
Lara M. Bonomi ◽  
Alan L. Schneyer
Keyword(s):  
Germ Cell ◽  
Germ Cells ◽  
Ovarian Function ◽  
Primordial Follicle ◽  
Biochemical Properties ◽  
The Body ◽  
Protein Isoforms ◽  
Primordial Follicles ◽  
Reduced Rate ◽  
Regulatory Functions

Abstract Follistatin (FST) is an antagonist of activin and related TGFβ superfamily members that has important reproductive actions as well as critical regulatory functions in other tissues and systems. FST is produced as three protein isoforms that differ in their biochemical properties and in their localization within the body. We created FST288-only mice that only express the short FST288 isoform and previously reported that females are subfertile, but have an excess of primordial follicles on postnatal day (PND) 8.5 that undergo accelerated demise in adults. We have now examined germ cell nest breakdown and primordial follicle formation in the critical PND 0.5–8.5 period to test the hypothesis that the excess primordial follicles derive from increased proliferation and decreased apoptosis during germ cell nest breakdown. Using double immunofluorescence microscopy we found that there is virtually no germ cell proliferation after birth in wild-type or FST288-only females. However, the entire process of germ cell nest breakdown was extended in time (through at least PND 8.5) and apoptosis was significantly reduced in FST288-only females. In addition, FST288-only females are born with more germ cells within the nests. Thus, the excess primordial follicles in FST288-only mice derive from a greater number of germ cells at birth as well as a reduced rate of apoptosis during nest breakdown. These results also demonstrate that FST is critical for normal regulation of germ cell nest breakdown and that loss of the FST303 and/or FST315 isoforms leads to excess primordial follicles with accelerated demise, resulting in premature cessation of ovarian function.

scholarly journals Overexpression of peroxisomal testis-specific 1 protein induces germ cell apoptosis and leads to infertility in male mice

2011 ◽  
Vol 22 (10) ◽  
pp. 1766-1779 ◽  
Author(s):  
Karina Kaczmarek ◽  
Maja Studencka ◽  
Andreas Meinhardt ◽  
Krzysztof Wieczerzak ◽  
Sven Thoms ◽  
...  
Keyword(s):  
Cell Death ◽  
Germ Cell ◽  
Germ Cells ◽  
Specific Gene ◽  
Male Mice ◽  
Terminal Part ◽  
Male Germ Cells ◽  
Germ Cell Apoptosis ◽  
Induced Apoptosis

 Peroxisomal testis-specific 1 gene (Pxt1) is the only male germ cell–specific gene that encodes a peroxisomal protein known to date. To elucidate the role of Pxt1 in spermatogenesis, we generated transgenic mice expressing a c-MYC-PXT1 fusion protein under the control of the PGK2 promoter. Overexpression of Pxt1 resulted in induction of male germ cells’ apoptosis mainly in primary spermatocytes, finally leading to male infertility. This prompted us to analyze the proapoptotic character of mouse PXT1, which harbors a BH3-like domain in the N-terminal part. In different cell lines, the overexpression of PXT1 also resulted in a dramatic increase of apoptosis, whereas the deletion of the BH3-like domain significantly reduced cell death events, thereby confirming that the domain is functional and essential for the proapoptotic activity of PXT1. Moreover, we demonstrated that PXT1 interacts with apoptosis regulator BAT3, which, if overexpressed, can protect cells from the PXT1-induced apoptosis. The PXT1-BAT3 association leads to PXT1 relocation from the cytoplasm to the nucleus. In summary, we demonstrated that PXT1 induces apoptosis via the BH3-like domain and that this process is inhibited by BAT3.

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