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1.
Cell ; 187(5): 1109-1126.e21, 2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38382525

RESUMO

Oocytes are among the longest-lived cells in the body and need to preserve their cytoplasm to support proper embryonic development. Protein aggregation is a major threat for intracellular homeostasis in long-lived cells. How oocytes cope with protein aggregation during their extended life is unknown. Here, we find that mouse oocytes accumulate protein aggregates in specialized compartments that we named endolysosomal vesicular assemblies (ELVAs). Combining live-cell imaging, electron microscopy, and proteomics, we found that ELVAs are non-membrane-bound compartments composed of endolysosomes, autophagosomes, and proteasomes held together by a protein matrix formed by RUFY1. Functional assays revealed that in immature oocytes, ELVAs sequester aggregated proteins, including TDP-43, and degrade them upon oocyte maturation. Inhibiting degradative activity in ELVAs leads to the accumulation of protein aggregates in the embryo and is detrimental for embryo survival. Thus, ELVAs represent a strategy to safeguard protein homeostasis in long-lived cells.


Assuntos
Vesículas Citoplasmáticas , Oócitos , Agregados Proteicos , Animais , Feminino , Camundongos , Autofagossomos , Vesículas Citoplasmáticas/metabolismo , Lisossomos/metabolismo , Oócitos/citologia , Oócitos/metabolismo , Complexo de Endopeptidases do Proteassoma , Proteólise
2.
Cell ; 187(21): 6088-6103.e18, 2024 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-39214079

RESUMO

5-Methylcytosine (5mC) is an established epigenetic mark in vertebrate genomic DNA, but whether its oxidation intermediates formed during TET-mediated DNA demethylation possess an instructive role of their own that is also physiologically relevant remains unresolved. Here, we reveal a 5-formylcytosine (5fC) nuclear chromocenter, which transiently forms during zygotic genome activation (ZGA) in Xenopus and mouse embryos. We identify this chromocenter as the perinucleolar compartment, a structure associated with RNA Pol III transcription. In Xenopus embryos, 5fC is highly enriched on Pol III target genes activated at ZGA, notably at oocyte-type tandem arrayed tRNA genes. By manipulating Tet and Tdg enzymes, we show that 5fC is required as a regulatory mark to promote Pol III recruitment as well as tRNA expression. Concordantly, 5fC modification of a tRNA transgene enhances its expression in vivo. The results establish 5fC as an activating epigenetic mark during zygotic reprogramming of Pol III gene expression.


Assuntos
Citosina , Epigênese Genética , RNA Polimerase III , Zigoto , Animais , Citosina/metabolismo , Citosina/análogos & derivados , Camundongos , Zigoto/metabolismo , RNA Polimerase III/metabolismo , RNA Polimerase III/genética , RNA de Transferência/metabolismo , RNA de Transferência/genética , Xenopus laevis/metabolismo , Xenopus laevis/embriologia , Xenopus laevis/genética , Xenopus/metabolismo , Xenopus/embriologia , Xenopus/genética , Feminino , Reprogramação Celular , Regulação da Expressão Gênica no Desenvolvimento , Oócitos/metabolismo
3.
Cell ; 186(24): 5308-5327.e25, 2023 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-37922900

RESUMO

Mammalian oocytes are filled with poorly understood structures called cytoplasmic lattices. First discovered in the 1960s and speculated to correspond to mammalian yolk, ribosomal arrays, or intermediate filaments, their function has remained enigmatic to date. Here, we show that cytoplasmic lattices are sites where oocytes store essential proteins for early embryonic development. Using super-resolution light microscopy and cryoelectron tomography, we show that cytoplasmic lattices are composed of filaments with a high surface area, which contain PADI6 and subcortical maternal complex proteins. The lattices associate with many proteins critical for embryonic development, including proteins that control epigenetic reprogramming of the preimplantation embryo. Loss of cytoplasmic lattices by knocking out PADI6 or the subcortical maternal complex prevents the accumulation of these proteins and results in early embryonic arrest. Our work suggests that cytoplasmic lattices enrich maternally provided proteins to prevent their premature degradation and cellular activity, thereby enabling early mammalian development.


Assuntos
Oócitos , Proteínas , Gravidez , Animais , Feminino , Oócitos/metabolismo , Proteínas/metabolismo , Embrião de Mamíferos/metabolismo , Citoesqueleto , Ribossomos , Desenvolvimento Embrionário , Mamíferos
4.
Cell ; 185(14): 2576-2590.e12, 2022 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-35623357

RESUMO

Mouse germline cysts, on average, develop into six oocytes supported by 24 nurse cells that transfer cytoplasm and organelles to generate a Balbiani body. We showed that between E14.5 and P5, cysts periodically activate some nurse cells to begin cytoplasmic transfer, which causes them to shrink and turnover within 2 days. Nurse cells die by a programmed cell death (PCD) pathway involving acidification, similar to Drosophila nurse cells, and only infrequently by apoptosis. Prior to initiating transfer, nurse cells co-cluster by scRNA-seq with their pro-oocyte sisters, but during their final 2 days, they cluster separately. The genes promoting oocyte development and nurse cell PCD are upregulated, whereas the genes that repress transfer, such as Tex14, and oocyte factors, such as Nobox and Lhx8, are under-expressed. The transferred nurse cell centrosomes build a cytocentrum that establishes a large microtubule aster in the primordial oocyte that organizes the Balbiani body, defining the earliest oocyte polarity.


Assuntos
Linhagem da Célula , Cistos , Oócitos , Animais , Apoptose , Crescimento Celular , Cistos/genética , Cistos/metabolismo , Citoplasma/metabolismo , Drosophila melanogaster , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Camundongos , Oócitos/citologia , Oócitos/metabolismo , Ovário/citologia , Ovário/embriologia , Ovário/metabolismo
5.
Cell ; 185(8): 1308-1324.e23, 2022 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-35325593

RESUMO

Asymmetric localization of oskar ribonucleoprotein (RNP) granules to the oocyte posterior is crucial for abdominal patterning and germline formation in the Drosophila embryo. We show that oskar RNP granules in the oocyte are condensates with solid-like physical properties. Using purified oskar RNA and scaffold proteins Bruno and Hrp48, we confirm in vitro that oskar granules undergo a liquid-to-solid phase transition. Whereas the liquid phase allows RNA incorporation, the solid phase precludes incorporation of additional RNA while allowing RNA-dependent partitioning of client proteins. Genetic modification of scaffold granule proteins or tethering the intrinsically disordered region of human fused in sarcoma (FUS) to oskar mRNA allowed modulation of granule material properties in vivo. The resulting liquid-like properties impaired oskar localization and translation with severe consequences on embryonic development. Our study reflects how physiological phase transitions shape RNA-protein condensates to regulate the localization and expression of a maternal RNA that instructs germline formation.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila/metabolismo , Embrião não Mamífero/metabolismo , Animais , Grânulos de Ribonucleoproteínas Citoplasmáticas , Drosophila/embriologia , Proteínas de Drosophila/genética , Desenvolvimento Embrionário , Oócitos/metabolismo , RNA/metabolismo
6.
Cell ; 184(11): 2860-2877.e22, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-33964210

RESUMO

Most human embryos are aneuploid. Aneuploidy frequently arises during the early mitotic divisions of the embryo, but its origin remains elusive. Human zygotes that cluster their nucleoli at the pronuclear interface are thought to be more likely to develop into healthy euploid embryos. Here, we show that the parental genomes cluster with nucleoli in each pronucleus within human and bovine zygotes, and clustering is required for the reliable unification of the parental genomes after fertilization. During migration of intact pronuclei, the parental genomes polarize toward each other in a process driven by centrosomes, dynein, microtubules, and nuclear pore complexes. The maternal and paternal chromosomes eventually cluster at the pronuclear interface, in direct proximity to each other, yet separated. Parental genome clustering ensures the rapid unification of the parental genomes on nuclear envelope breakdown. However, clustering often fails, leading to chromosome segregation errors and micronuclei, incompatible with healthy embryo development.


Assuntos
Embrião de Mamíferos/metabolismo , Desenvolvimento Embrionário/genética , Aneuploidia , Animais , Bovinos , Nucléolo Celular/metabolismo , Núcleo Celular/metabolismo , Centrossomo/metabolismo , Segregação de Cromossomos/fisiologia , Cromossomos/metabolismo , Fertilização/genética , Humanos , Masculino , Microtúbulos/metabolismo , Mitose , Oócitos/metabolismo , Espermatozoides/metabolismo , Zigoto/metabolismo
7.
Cell ; 184(19): 4904-4918.e11, 2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34433012

RESUMO

Selfish centromere DNA sequences bias their transmission to the egg in female meiosis. Evolutionary theory suggests that centromere proteins evolve to suppress costs of this "centromere drive." In hybrid mouse models with genetically different maternal and paternal centromeres, selfish centromere DNA exploits a kinetochore pathway to recruit microtubule-destabilizing proteins that act as drive effectors. We show that such functional differences are suppressed by a parallel pathway for effector recruitment by heterochromatin, which is similar between centromeres in this system. Disrupting the kinetochore pathway with a divergent allele of CENP-C reduces functional differences between centromeres, whereas disrupting heterochromatin by CENP-B deletion amplifies the differences. Molecular evolution analyses using Murinae genomes identify adaptive evolution in proteins in both pathways. We propose that centromere proteins have recurrently evolved to minimize the kinetochore pathway, which is exploited by selfish DNA, relative to the heterochromatin pathway that equalizes centromeres, while maintaining essential functions.


Assuntos
Proteína B de Centrômero/metabolismo , Centrômero/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Alelos , Sequência de Aminoácidos , Animais , Evolução Biológica , Sistemas CRISPR-Cas/genética , Proteína Centromérica A/metabolismo , Proteínas Cromossômicas não Histona/química , Cromossomos de Mamíferos/metabolismo , Feminino , Heterocromatina/metabolismo , Cinetocoros/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Modelos Biológicos , Oócitos/metabolismo , Domínios Proteicos
8.
Cell ; 184(13): 3528-3541.e12, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-33984278

RESUMO

Nucleotide-binding, leucine-rich repeat receptors (NLRs) are major immune receptors in plants and animals. Upon activation, the Arabidopsis NLR protein ZAR1 forms a pentameric resistosome in vitro and triggers immune responses and cell death in plants. In this study, we employed single-molecule imaging to show that the activated ZAR1 protein can form pentameric complexes in the plasma membrane. The ZAR1 resistosome displayed ion channel activity in Xenopus oocytes in a manner dependent on a conserved acidic residue Glu11 situated in the channel pore. Pre-assembled ZAR1 resistosome was readily incorporated into planar lipid-bilayers and displayed calcium-permeable cation-selective channel activity. Furthermore, we show that activation of ZAR1 in the plant cell led to Glu11-dependent Ca2+ influx, perturbation of subcellular structures, production of reactive oxygen species, and cell death. The results thus support that the ZAR1 resistosome acts as a calcium-permeable cation channel to trigger immunity and cell death.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/imunologia , Arabidopsis/metabolismo , Cálcio/metabolismo , Proteínas de Transporte/metabolismo , Resistência à Doença/imunologia , Imunidade Vegetal , Transdução de Sinais , Animais , Morte Celular , Membrana Celular/metabolismo , Permeabilidade da Membrana Celular , Ácido Glutâmico/metabolismo , Bicamadas Lipídicas/metabolismo , Oócitos/metabolismo , Células Vegetais/metabolismo , Multimerização Proteica , Protoplastos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Imagem Individual de Molécula , Vacúolos/metabolismo , Xenopus
9.
Annu Rev Biochem ; 89: 695-715, 2020 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-32569527

RESUMO

The zona pellucida (ZP) is an extracellular matrix that surrounds all mammalian oocytes, eggs, and early embryos and plays vital roles during oogenesis, fertilization, and preimplantation development. The ZP is composed of three or four glycosylated proteins, ZP1-4, that are synthesized, processed, secreted, and assembled into long, cross-linked fibrils by growing oocytes. ZP proteins have an immunoglobulin-like three-dimensional structure and a ZP domain that consists of two subdomains, ZP-N and ZP-C, with ZP-N of ZP2 and ZP3 required for fibril assembly. A ZP2-ZP3 dimer is located periodically along ZP fibrils that are cross-linked by ZP1, a protein with a proline-rich N terminus. Fibrils in the inner and outer regions of the ZP are oriented perpendicular and parallel to the oolemma, respectively, giving the ZP a multilayered appearance. Upon fertilization of eggs, modification of ZP2 and ZP3 results in changes in the ZP's physical and biological properties that have important consequences. Certain structural features of ZP proteins suggest that they may be amyloid-like proteins.


Assuntos
Proteínas Amiloidogênicas/química , Glicoproteínas da Zona Pelúcida/química , Zigoto/metabolismo , Proteínas Amiloidogênicas/genética , Proteínas Amiloidogênicas/metabolismo , Animais , Embrião de Mamíferos/metabolismo , Embrião de Mamíferos/ultraestrutura , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Oócitos/crescimento & desenvolvimento , Oócitos/metabolismo , Oócitos/ultraestrutura , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Multimerização Proteica , Zona Pelúcida/metabolismo , Zona Pelúcida/ultraestrutura , Glicoproteínas da Zona Pelúcida/genética , Glicoproteínas da Zona Pelúcida/metabolismo , Zigoto/crescimento & desenvolvimento , Zigoto/ultraestrutura
10.
Annu Rev Biochem ; 89: 255-282, 2020 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-32259458

RESUMO

Facultative heterochromatin (fHC) concerns the developmentally regulated heterochromatinization of different regions of the genome and, in the case of the mammalian X chromosome and imprinted loci, of only one allele of a homologous pair. The formation of fHC participates in the timely repression of genes, by resisting strong trans activators. In this review, we discuss the molecular mechanisms underlying the establishment and maintenance of fHC in mammals using a mouse model. We focus on X-chromosome inactivation (XCI) as a paradigm for fHC but also relate it to genomic imprinting and homeobox (Hox) gene cluster repression. A vital role for noncoding transcription and/or transcripts emerges as the general principle of triggering XCI and canonical imprinting. However, other types of fHC are established through an unknown mechanism, independent of noncoding transcription (Hox clusters and noncanonical imprinting). We also extensively discuss polycomb-group repressive complexes (PRCs), which frequently play a vital role in fHC maintenance.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Impressão Genômica , Heterocromatina/metabolismo , Proteínas do Grupo Polycomb/genética , Inativação do Cromossomo X , Cromossomo X/metabolismo , Animais , Montagem e Desmontagem da Cromatina , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Embrião de Mamíferos , Feminino , Inativação Gênica , Heterocromatina/química , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Masculino , Oócitos/citologia , Oócitos/crescimento & desenvolvimento , Oócitos/metabolismo , Proteínas do Grupo Polycomb/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Espermatozoides/citologia , Espermatozoides/crescimento & desenvolvimento , Espermatozoides/metabolismo , Cromossomo X/química
11.
Nat Rev Mol Cell Biol ; 24(1): 27-44, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36068367

RESUMO

During fertilization, the egg and the sperm are supposed to contribute precisely one copy of each chromosome to the embryo. However, human eggs frequently contain an incorrect number of chromosomes - a condition termed aneuploidy, which is much more prevalent in eggs than in either sperm or in most somatic cells. In turn, aneuploidy in eggs is a leading cause of infertility, miscarriage and congenital syndromes. Aneuploidy arises as a consequence of aberrant meiosis during egg development from its progenitor cell, the oocyte. In human oocytes, chromosomes often segregate incorrectly. Chromosome segregation errors increase in women from their mid-thirties, leading to even higher levels of aneuploidy in eggs from women of advanced maternal age, ultimately causing age-related infertility. Here, we cover the two main areas that contribute to aneuploidy: (1) factors that influence the fidelity of chromosome segregation in eggs of women from all ages and (2) factors that change in response to reproductive ageing. Recent discoveries reveal new error-causing pathways and present a framework for therapeutic strategies to extend the span of female fertility.


Assuntos
Infertilidade , Sêmen , Animais , Feminino , Masculino , Humanos , Oócitos/metabolismo , Aneuploidia , Meiose , Envelhecimento/genética , Segregação de Cromossomos/genética , Infertilidade/metabolismo , Mamíferos
12.
Cell ; 180(3): 585-600.e19, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32004457

RESUMO

Molecular mechanisms of ovarian aging and female age-related fertility decline remain unclear. We surveyed the single-cell transcriptomic landscape of ovaries from young and aged non-human primates (NHPs) and identified seven ovarian cell types with distinct gene-expression signatures, including oocyte and six types of ovarian somatic cells. In-depth dissection of gene-expression dynamics of oocytes revealed four subtypes at sequential and stepwise developmental stages. Further analysis of cell-type-specific aging-associated transcriptional changes uncovered the disturbance of antioxidant signaling specific to early-stage oocytes and granulosa cells, indicative of oxidative damage as a crucial factor in ovarian functional decline with age. Additionally, inactivated antioxidative pathways, increased reactive oxygen species, and apoptosis were observed in granulosa cells from aged women. This study provides a comprehensive understanding of the cell-type-specific mechanisms underlying primate ovarian aging at single-cell resolution, revealing new diagnostic biomarkers and potential therapeutic targets for age-related human ovarian disorders.


Assuntos
Envelhecimento/genética , Ovário/fisiologia , Análise de Célula Única/métodos , Transcriptoma , Idoso , Animais , Antioxidantes/metabolismo , Apoptose/fisiologia , Atlas como Assunto , Biomarcadores , Linhagem Celular Tumoral , Feminino , Células da Granulosa/metabolismo , Humanos , Macaca fascicularis , Oócitos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/fisiologia
13.
Cell ; 180(6): 1212-1227.e14, 2020 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-32169215

RESUMO

The paternal genome undergoes a massive exchange of histone with protamine for compaction into sperm during spermiogenesis. Upon fertilization, this process is potently reversed, which is essential for parental genome reprogramming and subsequent activation; however, it remains poorly understood how this fundamental process is initiated and regulated. Here, we report that the previously characterized splicing kinase SRPK1 initiates this life-beginning event by catalyzing site-specific phosphorylation of protamine, thereby triggering protamine-to-histone exchange in the fertilized oocyte. Interestingly, protamine undergoes a DNA-dependent phase transition to gel-like condensates and SRPK1-mediated phosphorylation likely helps open up such structures to enhance protamine dismissal by nucleoplasmin (NPM2) and enable the recruitment of HIRA for H3.3 deposition. Remarkably, genome-wide assay for transposase-accessible chromatin sequencing (ATAC-seq) analysis reveals that selective chromatin accessibility in both sperm and MII oocytes is largely erased in early pronuclei in a protamine phosphorylation-dependent manner, suggesting that SRPK1-catalyzed phosphorylation initiates a highly synchronized reorganization program in both parental genomes.


Assuntos
Cromatina/metabolismo , Protaminas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Proteínas de Ciclo Celular/metabolismo , Núcleo Celular/metabolismo , Cromatina/fisiologia , Montagem e Desmontagem da Cromatina/genética , Montagem e Desmontagem da Cromatina/fisiologia , Fertilização/genética , Histonas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oócitos/metabolismo , Oócitos/fisiologia , Fosforilação , Protamina Quinase/genética , Protamina Quinase/metabolismo , Protaminas/genética , Proteínas Serina-Treonina Quinases/fisiologia , Splicing de RNA/genética , Splicing de RNA/fisiologia , Espermatozoides/metabolismo , Fatores de Transcrição/metabolismo , Zigoto/metabolismo
14.
Cell ; 182(1): 127-144.e23, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32502394

RESUMO

Before zygotic genome activation (ZGA), the quiescent genome undergoes reprogramming to transition into the transcriptionally active state. However, the mechanisms underlying euchromatin establishment during early embryogenesis remain poorly understood. Here, we show that histone H4 lysine 16 acetylation (H4K16ac) is maintained from oocytes to fertilized embryos in Drosophila and mammals. H4K16ac forms large domains that control nucleosome accessibility of promoters prior to ZGA in flies. Maternal depletion of MOF acetyltransferase leading to H4K16ac loss causes aberrant RNA Pol II recruitment, compromises the 3D organization of the active genomic compartments during ZGA, and causes downregulation of post-zygotically expressed genes. Germline depletion of histone deacetylases revealed that other acetyl marks cannot compensate for H4K16ac loss in the oocyte. Moreover, zygotic re-expression of MOF was neither able to restore embryonic viability nor onset of X chromosome dosage compensation. Thus, maternal H4K16ac provides an instructive function to the offspring, priming future gene activation.


Assuntos
Histonas/metabolismo , Lisina/metabolismo , Ativação Transcricional/genética , Acetilação , Animais , Sequência de Bases , Segregação de Cromossomos/genética , Sequência Conservada , Mecanismo Genético de Compensação de Dose , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/embriologia , Drosophila melanogaster/genética , Embrião não Mamífero/metabolismo , Evolução Molecular , Feminino , Genoma , Histona Acetiltransferases/genética , Histona Acetiltransferases/metabolismo , Masculino , Mamíferos/genética , Camundongos , Mutação/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Nucleossomos/metabolismo , Oócitos/metabolismo , Regiões Promotoras Genéticas , RNA Polimerase II/metabolismo , Cromossomo X/metabolismo , Zigoto/metabolismo
15.
Cell ; 178(5): 1132-1144.e10, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31402175

RESUMO

Asymmetric division in female meiosis creates selective pressure favoring selfish centromeres that bias their transmission to the egg. This centromere drive can explain the paradoxical rapid evolution of both centromere DNA and centromere-binding proteins despite conserved centromere function. Here, we define a molecular pathway linking expanded centromeres to histone phosphorylation and recruitment of microtubule destabilizing factors, leading to detachment of selfish centromeres from spindle microtubules that would direct them to the polar body. Exploiting centromere divergence between species, we show that selfish centromeres in two hybrid mouse models use the same molecular pathway but modulate it differently to enrich destabilizing factors. Our results indicate that increasing microtubule destabilizing activity is a general strategy for drive in both models, but centromeres have evolved distinct mechanisms to increase that activity. Furthermore, we show that drive depends on slowing meiotic progression, suggesting that selfish centromeres can be suppressed by regulating meiotic timing.


Assuntos
Centrômero/genética , Meiose , Animais , Segregação de Cromossomos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microtúbulos/metabolismo , Oócitos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo
16.
Cell ; 177(6): 1463-1479.e18, 2019 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-31080065

RESUMO

Segregation of maternal determinants within the oocyte constitutes the first step in embryo patterning. In zebrafish oocytes, extensive ooplasmic streaming leads to the segregation of ooplasm from yolk granules along the animal-vegetal axis of the oocyte. Here, we show that this process does not rely on cortical actin reorganization, as previously thought, but instead on a cell-cycle-dependent bulk actin polymerization wave traveling from the animal to the vegetal pole of the oocyte. This wave functions in segregation by both pulling ooplasm animally and pushing yolk granules vegetally. Using biophysical experimentation and theory, we show that ooplasm pulling is mediated by bulk actin network flows exerting friction forces on the ooplasm, while yolk granule pushing is achieved by a mechanism closely resembling actin comet formation on yolk granules. Our study defines a novel role of cell-cycle-controlled bulk actin polymerization waves in oocyte polarization via ooplasmic segregation.


Assuntos
Actinas/metabolismo , Ciclo Celular/fisiologia , Oócitos/metabolismo , Actinas/fisiologia , Animais , Polaridade Celular/fisiologia , Citoplasma/metabolismo , Gema de Ovo/fisiologia , Polimerização , Peixe-Zebra/embriologia , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Zigoto
17.
Cell ; 176(6): 1379-1392.e14, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30773315

RESUMO

Cell fate specification by lateral inhibition typically involves contact signaling through the Delta-Notch signaling pathway. However, whether this is the only signaling mode mediating lateral inhibition remains unclear. Here we show that in zebrafish oogenesis, a group of cells within the granulosa cell layer at the oocyte animal pole acquire elevated levels of the transcriptional coactivator TAZ in their nuclei. One of these cells, the future micropyle precursor cell (MPC), accumulates increasingly high levels of nuclear TAZ and grows faster than its surrounding cells, mechanically compressing those cells, which ultimately lose TAZ from their nuclei. Strikingly, relieving neighbor-cell compression by MPC ablation or aspiration restores nuclear TAZ accumulation in neighboring cells, eventually leading to MPC re-specification from these cells. Conversely, MPC specification is defective in taz-/- follicles. These findings uncover a novel mode of lateral inhibition in cell fate specification based on mechanical signals controlling TAZ activity.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Oogênese/fisiologia , Proteínas de Peixe-Zebra/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Comunicação Celular/fisiologia , Diferenciação Celular/fisiologia , Linhagem da Célula , Núcleo Celular/metabolismo , Feminino , Células da Granulosa/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Oócitos/metabolismo , Oócitos/fisiologia , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismo , Ativação Transcricional/fisiologia , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/antagonistas & inibidores
18.
Cell ; 174(5): 1082-1094.e12, 2018 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-30057117

RESUMO

Although animals have evolved multiple mechanisms to suppress transposons, "leaky" mobilizations that cause mutations and diseases still occur. This suggests that transposons employ specific tactics to accomplish robust propagation. By directly tracking mobilization, we show that, during a short and specific time window of oogenesis, retrotransposons achieve massive amplification via a cell-type-specific targeting strategy. Retrotransposons rarely mobilize in undifferentiated germline stem cells. However, as oogenesis proceeds, they utilize supporting nurse cells-which are highly polyploid and eventually undergo apoptosis-as factories to massively manufacture invading products. Moreover, retrotransposons rarely integrate into nurse cells themselves but, instead, via microtubule-mediated transport, they preferentially target the DNA of the interconnected oocytes. Blocking microtubule-dependent intercellular transport from nurse cells significantly alleviates damage to the oocyte genome. Our data reveal that parasitic genomic elements can efficiently hijack a host developmental process to propagate robustly, thereby driving evolutionary change and causing disease.


Assuntos
Drosophila melanogaster/genética , Elementos Nucleotídeos Longos e Dispersos , Oogênese , RNA Interferente Pequeno , Retroelementos , Retroviridae/genética , Animais , Proteínas de Drosophila , Feminino , Biblioteca Gênica , Inativação Gênica , Células Germinativas , Proteínas de Fluorescência Verde/metabolismo , Hibridização in Situ Fluorescente , Masculino , Oócitos/metabolismo , Células-Tronco/metabolismo
19.
Cell ; 169(3): 457-469.e13, 2017 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-28431246

RESUMO

Fat metabolism has been linked to fertility and reproductive adaptation in animals and humans, and environmental sex determination potentially plays a role in the process. To investigate the impact of fatty acids (FA) on sex determination and reproductive development, we examined and observed an impact of FA synthesis and mobilization by lipolysis in somatic tissues on oocyte fate in Caenorhabditis elegans. The subsequent genetic analysis identified ACS-4, an acyl-CoA synthetase and its FA-CoA product, as key germline factors that mediate the role of FA in promoting oocyte fate through protein myristoylation. Further tests indicated that ACS-4-dependent protein myristoylation perceives and translates the FA level into regulatory cues that modulate the activities of MPK-1/MAPK and key factors in the germline sex-determination pathway. These findings, including a similar role of ACS-4 in a male/female species, uncover a likely conserved mechanism by which FA, an environmental factor, regulates sex determination and reproductive development.


Assuntos
Acetato-CoA Ligase/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiologia , Ácidos Graxos/metabolismo , Ácido Mirístico/metabolismo , Processamento de Proteína Pós-Traducional , Processos de Determinação Sexual , Acetato-CoA Ligase/genética , Animais , Proteínas de Caenorhabditis elegans/genética , Mutação , Oócitos/metabolismo
20.
Genes Dev ; 38(9-10): 436-454, 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38866556

RESUMO

Genome organization can regulate gene expression and promote cell fate transitions. The differentiation of germline stem cells (GSCs) to oocytes in Drosophila involves changes in genome organization mediated by heterochromatin and the nuclear pore complex (NPC). Heterochromatin represses germ cell genes during differentiation, and NPCs anchor these silenced genes to the nuclear periphery, maintaining silencing to allow for oocyte development. Surprisingly, we found that genome organization also contributes to NPC formation, mediated by the transcription factor Stonewall (Stwl). As GSCs differentiate, Stwl accumulates at boundaries between silenced and active gene compartments. Stwl at these boundaries plays a pivotal role in transitioning germ cell genes into a silenced state and activating a group of oocyte genes and nucleoporins (Nups). The upregulation of these Nups during differentiation is crucial for NPC formation and further genome organization. Thus, cross-talk between genome architecture and NPCs is essential for successful cell fate transitions.


Assuntos
Diferenciação Celular , Proteínas de Drosophila , Genoma de Inseto , Poro Nuclear , Oogênese , Animais , Oogênese/genética , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Diferenciação Celular/genética , Poro Nuclear/metabolismo , Poro Nuclear/genética , Genoma de Inseto/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Feminino , Drosophila melanogaster/genética , Oócitos/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Drosophila/genética , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/genética
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