Oocytes and early embryos selectively express the survival factor BCL2L10. Guillemin Y et al. Apoptosis has been reported in oocytes and human preimplantation embryos both in vitro and in vivo. BCL-2 family proteins are likely to play a pivotal role in controlling oocyte and early embryo degeneration. However, no BCL-2-related survival factors have been identified that would specifically function during oocyte maturation, after fertilization and during early embryogenesis. Here, we performed a comprehensive tissue expression pattern analysis of the BCL-2 family at the mRNA level. While expression of various members was detected in human oocytes and during early primate embryogenesis, our data indicate that BCL2L10 is the predominant maternally loaded Bcl-2 family transcript, revealing an evolutionary conserved expression profile at the egg-to-zygote transition. We provide evidence that BCL2L10 is associated with the microtubule binding protein translationally controlled tumor protein and mitochondria, with a stage-specific redistribution along the pericortical regulatory ooplasm. In dying oocytes, BCL2L10 colocalized with proapoptotic BAX and neutralization of BCL2L10 accelerated oocyte death. We propose BCL2L10 as a novel and prime candidate related to oocyte maturation, fertility, and embryo developmental competence.
NCBI Summary:
The protein encoded by this gene belongs to the BCL-2 protein family. BCL-2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. The protein encoded by this gene contains conserved BH4, BH1 and BH2 domains. This protein can interact with other members of BCL-2 protein family including BCL2, BCL2L1/BCL-X(L), and BAX. Overexpression of this gene has been shown to suppress cell apoptosis possibly through the prevention of cytochrome C release from the mitochondria, and thus activating caspase-3 activation. The mouse counterpart of this protein is found to interact with Apaf1 and forms a protein complex with Caspase 9, which suggests the involvement of this protein in APAF1 and CASPASE 9 related apoptotic pathway. [provided by RefSeq, Jul 2008]
General function
Cell death/survival, Anti-apoptotic, Apoptosis
Comment
characterization of unique signature sequences in the divergent maternal Protein BCL2L10. Guillemin Y et al. Insertions or deletions (indels) of amino acids residues have been recognized as an important source of genetic and structural divergence between paralogous Bcl-2 family members. However, these signature sequences have not so far been extensively investigated amongst orthologous Bcl-2 family proteins. Bcl2l10 is an anti-apoptotic member of the Bcl-2 family that has evolved rapidly throughout the vertebrate lineage, and which shows conserved abundant expression in eggs and oocytes. In this paper, we have unraveled two major sites of divergence between human Bcl2l10 and its vertebrate homologues. The first one provides length variation at the N-terminus (before the BH4 domain), and the second one is located between the predicted a5-a6 pore-forming helices, providing an unprecedented case in the superfamily of helix-bundled pore-forming proteins. These two particular indels were studied phylogenetically, and through biochemical and cell biological techniques, including truncation and site-directed mutagenesis. While deletion of the N-terminal extension had no significant functional impact in HeLa cells, our results suggest that the human Bcl2l10 protein evolved a calcium-binding motif in its a5-a6 interhelical region by acquiring critical negatively charged residues. Considering the reliance of female eggs on calcium-dependent proteins and calcium-regulated processes, and the exceptional longevity of oocytes in the primate lineage, we propose that this micro-structural variation may be an adaptive feature associated with high maternal expression of this Bcl-2 family member.
Diva, a Bcl-2 homologue that binds directly to Apaf-1 and induces BH3-independent cell death. Inohara N et al. We have identified and characterized Diva, which is a novel regulator of apoptosis. Sequence analysis revealed that Diva is a member of the Bcl-2 family of proteins containing Bcl-2 homology domain 1, 2, 3, and 4 (BH1, BH2, BH3, and BH4) regions and a carboxyl-terminal hydrophobic domain. The expression of Diva mRNA was detected in multiple embryonic tissues but was restricted to the ovary and testis in adult mice. The expression of Diva promoted the death of 293T, Ramsey, and T47D cells as well as that of primary sensory neurons, indicating that Diva is a proapoptotic protein. Significantly, Diva lacks critical residues in the conserved BH3 region that mediate the interaction between BH3-containing proapoptotic Bcl-2 homologues and their prosurvival binding partners. Consistent with this, Diva did not bind to cellular Bcl-2 family members including Bcl-2, Bcl-XL, Bcl-w, Mcl-1, and A1/Bfl-1. Furthermore, mutants of Diva lacking the BH3 region fully retained their proapoptotic activity, confirming that Diva promotes apoptosis in a BH3-independent manner. Significantly, Diva interacted with a viral Bcl-2 homologue (vBcl-2) encoded by the Kaposi's sarcoma-associated herpesvirus. Consistent with these associations, apoptosis induced by Diva was inhibited by vBcl-2 but not by Bcl-XL. Importantly, Diva interacted with Apaf-1, an adapter molecule that activates caspase-9, a central death protease of the apoptotic pathway. The expression of Diva inhibited the binding of Bcl-XL to Apaf-1, as determined by immunoprecipitation assays. Thus, Diva represents a novel type of proapoptotic Bcl-2 homologue that promotes apoptosis independently of the BH3 region through direct binding to Apaf-1, thus preventing Bcl-XL from binding to the caspase-9 regulator Apaf-1.
Cellular localization
Cytoplasmic
Comment
Ovarian function
Oocyte maturation, Early embryo development
Comment
Role of BCL2L10 in regulating buffalo (Bubalus bubalis) oocyte maturation. Huang YL et al. (2018) It has been reported that BCL2L10 is abundantly and specifically expressed in adult human and mouse oocytes and played a very important role in oocytes maturation and early embryonic development. This study is to investigate the expression pattern of BCL2L10 in buffalo ovaries and its effect on the in vitro maturation of buffalo oocytes, so as to dissect mechanism of oocytes maturation and provide theoretical guidance for improvement of the in vitro maturation of buffalo oocytes. The results showed that BCL2L10 gene was enriched in ovary and the expression of BCL2L10 was oocyte specific and up-regulated during oocyte maturation. BCL2L10 protein and mRNA were detectable in buffalo early embryos, upregulated at 2-cell to 8-cell stages and down-regulated in the later stages. Knockdown of BCL2L10 by RNA interference resulted in a significant decrease in the maturation rate (33.5%) and cleavage rate (37.52%) of buffalo oocytes coupled with up-regulation of apoptosis-related gene Caspase-9. We concluded that BCL2L10 is a candidate associated with buffalo oocyte maturation.//////////////////
Role of Bcl2-like 10 (Bcl2l10) in Regulating Mouse Oocyte Maturation. Yoon SJ et al. Previously, we have shown that Bcl2l10 is highly expressed in metaphase II (MII) stage oocytes. The objective of this study was to characterize Bcl2l10 expression in ovaries and to examine the function of Bcl2l10 in oocyte maturation using RNA interference (RNAi). Bcl2l10 transcript expression was ovary- and oocyte-specific. Bcl2l10 was highly expressed in oocytes and pronuclear stage embryos; however, its expression decreased at the two-cell stage and dramatically disappeared thereafter. Microinjection of Bcl2l10 double-stranded RNA (dsRNA) into the cytoplasm of germinal vesicle (GV) oocytes resulted in a marked decrease in Bcl2l10 mRNA and protein and MI arrest (78.9%). Most MI-arrested oocytes exhibited abnormalities in their spindles and chromosome configurations. Bcl2l10 RNAi had an obvious effect on the activity of maturation-promoting factor (MPF) but not on that of mitogen-activated protein kinase (MAPK). We concluded that the role of Bcl2l10 is strongly associated with oocyte maturation, especially at the MI-MII transition.
Expression regulated by
Comment
Ovarian localization
Oocyte
Comment
Decreases during oocyte development based on DNA microarray data.///////////
Genomewide discovery and classification of candidate ovarian fertility genes in the mouse. Gallardo TD et al. Female infertility syndromes are among the most prevalent chronic health disorders in women, but their genetic basis remains unknown because of uncertainty regarding the number and identity of ovarian factors controlling the assembly, preservation, and maturation of ovarian follicles. To systematically discover ovarian fertility genes en masse, we employed a mouse model (Foxo3) in which follicles are assembled normally but then undergo synchronous activation. We developed a microarray-based approach for the systematic discovery of tissue-specific genes and, by applying it to Foxo3 ovaries and other samples, defined a surprisingly large set of ovarian factors (n = 348, approximately 1% of the mouse genome). This set included the vast majority of known ovarian factors, 44% of which when mutated produce female sterility phenotypes, but most were novel. Comparative profiling of other tissues, including microdissected oocytes and somatic cells, revealed distinct gene classes and provided new insights into oogenesis and ovarian function, demonstrating the utility of our approach for tissue-specific gene discovery. This study will thus facilitate comprehensive analyses of follicle development, ovarian function, and female infertility. This is an oocyte-specific gene.
Species: mouse
Mutation name: None
type: null mutation fertility: fertile Comment: Murine ovarian development is not affected by inactivation of the bcl-2 family member diva. Russell HR et al. Diva (also called Boo/Bcl-B) is a member of the Bcl-2 gene family and most likely functions during apoptosis. Diva is highly expressed in the ovary, and both pro- and antiapoptotic functions have been ascribed to this protein. To determine the role of Diva during murine development, we used gene targeting to inactivate DIVA: The Diva-null mice are born at the expected ratios, are fertile, and have no obvious histological abnormalities, and long-term survival did not differ from littermate controls. Additionally, Diva was not required for apoptosis occurring from genotoxic insult in the ovaries or other organs. Thus, Diva is not critical for the normal development of the ovaries, or in its absence its function is subserved by another protein.