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1.
Cell Rep ; 42(2): 112106, 2023 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-36773294

RESUMO

Drak2-deficient (Drak2-/-) mice are resistant to multiple models of autoimmunity yet effectively eliminate pathogens and tumors. Thus, DRAK2 represents a potential target to treat autoimmune diseases. However, the mechanisms by which DRAK2 contributes to autoimmunity, particularly type 1 diabetes (T1D), remain unresolved. Here, we demonstrate that resistance to T1D in non-obese diabetic (NOD) mice is due to the absence of Drak2 in T cells and requires the presence of regulatory T cells (Tregs). Contrary to previous hypotheses, we show that DRAK2 does not limit TCR signaling. Rather, DRAK2 regulates IL-2 signaling by inhibiting STAT5A phosphorylation. We further demonstrate that enhanced sensitivity to IL-2 in the absence of Drak2 augments thymic Treg development. Overall, our data indicate that DRAK2 contributes to autoimmunity in multiple ways by regulating thymic Treg development and by impacting the sensitivity of conventional T cells to Treg-mediated suppression.


Assuntos
Doenças Autoimunes , Diabetes Mellitus Tipo 1 , Camundongos , Animais , Interleucina-2/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Linfócitos T Reguladores/metabolismo , Camundongos Endogâmicos NOD
2.
Cell Rep ; 38(10): 110482, 2022 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-35263574

RESUMO

Infection and vaccination repeatedly expose individuals to antigens that are conserved between influenza virus subtypes. Nevertheless, antibodies recognizing variable influenza epitopes greatly outnumber antibodies reactive against conserved epitopes. Elucidating factors contributing to the paucity of broadly reactive influenza antibodies remains a major obstacle for developing a universal influenza vaccine. Here, we report that inducing broadly reactive influenza antibodies increases autoreactive antibodies in humans and mice and exacerbates disease in four distinct models of autoimmune disease. Importantly, transferring broadly reactive influenza antibodies augments disease in the presence of inflammation or autoimmune susceptibility. Further, broadly reactive influenza antibodies spontaneously arise in mice with defects in B cell tolerance. Together, these data suggest that self-tolerance mechanisms limit the prevalence of broadly reactive influenza antibodies, which can exacerbate disease in the context of additional risk factors.


Assuntos
Vacinas contra Influenza , Influenza Humana , Infecções por Orthomyxoviridae , Animais , Anticorpos Neutralizantes , Anticorpos Antivirais , Autoimunidade , Epitopos , Glicoproteínas de Hemaglutininação de Vírus da Influenza , Humanos , Camundongos
3.
PLoS One ; 14(2): e0211244, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30807587

RESUMO

Expulsion of parasitic gastrointestinal nematodes requires diverse effector mechanisms coordinated by a Th2-type response. The evolutionarily conserved JmjC protein; Myc Induced Nuclear Antigen (Mina) has been shown to repress IL4, a key Th2 cytokine, suggesting Mina may negatively regulate nematode expulsion. Here we report that expulsion of the parasitic nematode Trichuris muris was indeed accelerated in Mina deficient mice. Unexpectedly, this was associated not with an elevated Th2- but rather an impaired Th1-type response. Further reciprocal bone marrow chimera and conditional KO experiments demonstrated that retarded parasite expulsion and a normal Th1-type response both required Mina in intestinal epithelial cells (IECs). Transcriptional profiling experiments in IECs revealed anti-microbial α-defensin peptides to be the major target of Mina-dependent retention of worms in infected mice. In vitro exposure to recombinant α-defensin peptides caused cytotoxic damage to whipworms. These results identify a latent IEC-intrinsic anthelmintic pathway actively constrained by Mina and point to α-defensins as important effectors that together with Mina may be attractive therapeutic targets for the control of nematode infection.


Assuntos
Células Epiteliais/metabolismo , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Trichuris/imunologia , Animais , Citocinas/análise , Células Epiteliais/citologia , Intestinos/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas de Neoplasias/deficiência , Proteínas Nucleares/deficiência , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Células Th1/citologia , Células Th1/imunologia , Células Th1/metabolismo , Células Th2/citologia , Células Th2/imunologia , Células Th2/metabolismo , Transcriptoma , Tricuríase/tratamento farmacológico , Tricuríase/imunologia , Tricuríase/patologia , Trichuris/efeitos dos fármacos , Trichuris/patogenicidade , alfa-Defensinas/genética , alfa-Defensinas/metabolismo
4.
Curr Opin Immunol ; 31: 38-43, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25282476

RESUMO

The JmjC protein Mina is an important immune response regulator. Classical forward genetics first discovered its immune role in 2009 in connection with the development of T helper 2 (Th2) cells. This prompted investigation into Mina's role in the two best-studied contexts where Th2 responses are essential: atopic asthma and helminth expulsion. In work focused on a mouse model of atopic asthma, Mina deficiency was found to ameliorate airway hyper-resistance and pulmonary inflammation. And, in a case-control study genetic variation at the human MINA locus was found to be associated with the development of childhood atopic asthma. Although the underlying cellular and molecular mechanism of Mina's involvement in pulmonary inflammation remains unknown, our recent work on parasitic helminth expulsion suggests the possibility that, rather than T cells, epithelial cells responding to TGFß may play the dominant role. Here we review the growing body of literature on the emerging Mina pathway in T cells and epithelial cells and attempt to set these into a broader context.


Assuntos
Asma/imunologia , Helmintíase/imunologia , Proteínas de Neoplasias/imunologia , Proteínas Nucleares/imunologia , Células Th2/imunologia , Fator de Crescimento Transformador beta/imunologia , Animais , Asma/genética , Asma/patologia , Dioxigenases , Modelos Animais de Doenças , Loci Gênicos/imunologia , Variação Genética/imunologia , Helmintíase/genética , Helmintíase/patologia , Histona Desmetilases , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Camundongos , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Células Th2/patologia , Fator de Crescimento Transformador beta/genética
5.
PLoS One ; 8(12): e80638, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24324617

RESUMO

Mina is an epigenetic gene regulatory protein known to function in multiple physiological and pathological contexts, including pulmonary inflammation, cell proliferation, cancer and immunity. We showed previously that the level of Mina gene expression is subject to natural genetic variation linked to 21 SNPs occurring in the Mina 5' region. In order to explore the mechanisms regulating Mina gene expression, we set out to molecularly characterize the Mina promoter in the region encompassing these SNPs. We used three kinds of assays--reporter, gel shift and chromatin immunoprecipitation--to analyze a 2 kb genomic fragment spanning the upstream and intron 1 regions flanking exon 1. Here we discovered a pair of Mina promoters (P1 and P2) and a P1-specific enhancer element (E1). Pharmacologic inhibition and siRNA knockdown experiments suggested that Sp1/3 transcription factors trigger Mina expression through additive activity targeted to a cluster of four Sp1/3 binding sites forming the P1 promoter. These results set the stage for comprehensive analysis of Mina gene regulation from the context of tissue specificity, the impact of inherited genetic variation and the nature of upstream signaling pathways.


Assuntos
Elementos Facilitadores Genéticos , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Regiões Promotoras Genéticas , Fator de Transcrição Sp1/genética , Fator de Transcrição Sp3/genética , Ativação Transcricional , Animais , Sequência de Bases , Sítios de Ligação , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Ensaio de Desvio de Mobilidade Eletroforética , Epigênese Genética , Genes Reporter , Luciferases/genética , Luciferases/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Polimorfismo de Nucleotídeo Único , Ligação Proteica , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Fator de Transcrição Sp1/antagonistas & inibidores , Fator de Transcrição Sp1/metabolismo , Fator de Transcrição Sp3/antagonistas & inibidores , Fator de Transcrição Sp3/metabolismo
6.
Nature ; 496(7446): 461-8, 2013 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-23467089

RESUMO

Despite their importance, the molecular circuits that control the differentiation of naive T cells remain largely unknown. Recent studies that reconstructed regulatory networks in mammalian cells have focused on short-term responses and relied on perturbation-based approaches that cannot be readily applied to primary T cells. Here we combine transcriptional profiling at high temporal resolution, novel computational algorithms, and innovative nanowire-based perturbation tools to systematically derive and experimentally validate a model of the dynamic regulatory network that controls the differentiation of mouse TH17 cells, a proinflammatory T-cell subset that has been implicated in the pathogenesis of multiple autoimmune diseases. The TH17 transcriptional network consists of two self-reinforcing, but mutually antagonistic, modules, with 12 novel regulators, the coupled action of which may be essential for maintaining the balance between TH17 and other CD4(+) T-cell subsets. Our study identifies and validates 39 regulatory factors, embeds them within a comprehensive temporal network and reveals its organizational principles; it also highlights novel drug targets for controlling TH17 cell differentiation.


Assuntos
Diferenciação Celular/genética , Redes Reguladoras de Genes/genética , Células Th17/citologia , Células Th17/metabolismo , Animais , Células Cultivadas , DNA/genética , DNA/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Técnicas de Silenciamento de Genes , Genoma/genética , Interferon gama/biossíntese , Interleucina-2/genética , Camundongos , Camundongos Endogâmicos C57BL , Nanofios , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes , Silício , Células Th17/imunologia , Fatores de Tempo , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Transcrição Gênica/genética , Receptor fas/metabolismo
7.
J Virol ; 86(8): 4151-7, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22318144

RESUMO

RNA interference (RNAi) is a critical component of many cellular antiviral responses in plants, invertebrates, and mammals. However, its in vivo role in host protection from the negative-sense RNA virus influenza virus type A (flu) is unclear. Here we have examined the role of RNAi in host defense to flu by analyzing Argonaute 1 and 3 double-knockout mice deficient in components of the RNA-induced silencing complex. Compared to littermate controls, flu-infected double-knockout mice exhibited increased mortality, consistent with more severe alveolitis and pneumonitis. These data indicate that optimal resistance to flu requires Argonaute 1 and/or 3. Enhanced mortality of double-knockout mice was not associated either with increased viral replication or with differential pulmonary recruitment or function of innate and adaptive immune cells. Given the absence of detectable immune defects, our results support the notion that the enhanced flu susceptibility of double-knockout mice arises from an intrinsic impairment in the ability of lung cells to tolerate flu-elicited inflammation.


Assuntos
Proteínas Argonautas/genética , Fatores de Iniciação em Eucariotos/genética , Predisposição Genética para Doença , Vírus da Influenza A/imunologia , Infecções por Orthomyxoviridae/genética , Animais , Humanos , Pulmão/imunologia , Pulmão/virologia , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infecções por Orthomyxoviridae/imunologia , Interferência de RNA , Replicação Viral
8.
J Immunol ; 187(10): 4987-97, 2011 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-22013112

RESUMO

Regulatory T cells (T(regs)) can suppress a wide variety of cell types, in diverse organ sites and inflammatory conditions. Whereas T(regs) possess multiple suppressive mechanisms, the number required for maximal function is unclear. Furthermore, whether any interrelationship or cross-regulatory mechanisms exist to orchestrate and control their utilization is unknown. In this study, we assessed the functional capacity of T(regs) lacking the ability to secrete both IL-10 and IL-35, which individually are required for maximal T(reg) activity. Surprisingly, IL-10/IL-35 double-deficient T(regs) were fully functional in vitro and in vivo. Loss of IL-10 and IL-35 was compensated for by a concurrent increase in cathepsin E (Ctse) expression, enhanced TRAIL (Tnfsf10) expression, and soluble TRAIL release, rendering IL-10/IL-35 double-deficient T(regs) functionally dependent on TRAIL in vitro and in vivo. Lastly, whereas C57BL/6 T(regs) are normally IL-10/IL-35 dependent, BALB/c T(regs), which express high levels of cathepsin E and enhanced TRAIL expression, are partially TRAIL dependent by default. These data reveal that cross-regulatory pathways exist that control the utilization of suppressive mechanisms, thereby providing T(reg) functional plasticity.


Assuntos
Linfócitos T Reguladores/imunologia , Animais , Catepsina E/fisiologia , Células Cultivadas , Técnicas de Cocultura , Regulação para Baixo/genética , Regulação para Baixo/imunologia , Células HEK293 , Humanos , Interleucina-10/deficiência , Interleucina-10/metabolismo , Interleucinas/deficiência , Interleucinas/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia , Ligante Indutor de Apoptose Relacionado a TNF/fisiologia
9.
Growth Factors ; 29(4): 153-60, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21663408

RESUMO

Interleukin-4 (IL4) is a pleiotropic cytokine involved in host protection from gastrointestinal nematodes. Here, we review the structure, function, and evolutionary history of IL4. Cumulative evidence indicates that over 100 million years of eutherian mammalian evolution, IL4 has experienced multiple episodes of positive selection. We argue that IL4 may have evolved in conflict with pathogen-derived antagonists, and therefore diversified to escape antagonism while being constrained to maintain binding to its cellular receptors. Selective pressure driving IL4 diversification may have arisen from ancient episodes of conflict with parasitic worm-derived IL4 antagonists. Descendants of such antagonists may still equip the armamentarium of contemporary gastrointestinal nematodes.


Assuntos
Trato Gastrointestinal/parasitologia , Interleucina-4/imunologia , Interleucina-4/metabolismo , Nematoides/imunologia , Infecções por Nematoides/imunologia , Animais , Evolução Biológica , Evolução Molecular , Trato Gastrointestinal/imunologia , Interações Hospedeiro-Parasita , Humanos , Switching de Imunoglobulina , Interleucina-4/química , Interleucina-4/genética , Subunidade alfa de Receptor de Interleucina-4/metabolismo , Macrófagos/imunologia , Nematoides/metabolismo , Ligação Proteica , Seleção Genética
10.
Methods Mol Biol ; 707: 119-56, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21287333

RESUMO

To fully examine the functionality of a regulatory T cell (T(reg)) population, one needs to assess their ability to suppress in a variety of in vivo models. We describe five in vivo models that examine the suppressive capacity of T(regs) upon different target cell types. The advantages and disadvantages of each model including resources, time, and technical expertise required to execute each model are also described.


Assuntos
Modelos Animais de Doenças , Linfócitos T Reguladores/imunologia , Animais , Fatores de Transcrição Forkhead/genética , Genes RAG-1 , Camundongos
11.
J Immunol ; 182(10): 6121-8, 2009 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-19414764

RESUMO

Regulatory T cells (T(reg)) are believed to suppress conventional T cell (T(conv)) proliferation in vitro in a contact-dependent, cytokine-independent manner, based in part on experiments in which T(reg) and T(conv) are separated by a permeable membrane. We show that the production of IL-35, a novel inhibitory cytokine expressed by natural T(reg), increases substantially following contact with T(conv). Surprisingly, T(reg) were able to mediate potent suppression of T(conv) across a permeable membrane when placed in direct contact with T(conv) in the upper chamber of a Transwell plate. Suppression was IL-35 and IL-10 dependent, and T(conv) activation was required for maximal potentiation of T(reg) suppression. These data suggest that it is the induction of suppression, rather than the function of T(reg) that is obligatorily contact dependent.


Assuntos
Comunicação Celular/imunologia , Interleucina-10/imunologia , Interleucinas/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T/imunologia , Animais , Western Blotting , Proliferação de Células , Citometria de Fluxo , Imunoprecipitação , Ativação Linfocitária/imunologia , Camundongos , Camundongos Knockout , Reação em Cadeia da Polimerase Via Transcriptase Reversa
12.
Cell Mol Life Sci ; 66(16): 2603-22, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19390784

RESUMO

Regulatory T cells (Tregs) are a critical subset of T cells that mediate peripheral tolerance. There are two types of Tregs: natural Tregs, which develop in the thymus, and induced Tregs, which are derived from naive CD4(+) T cells in the periphery. Tregs utilize a variety of mechanisms to suppress the immune response. While Tregs are critical for the peripheral maintenance of potential autoreactive T cells, they can also be detrimental by preventing effective anti-tumor responses and sterilizing immunity against pathogens. In this review, we will discuss the development of natural and induced Tregs as well as the role of Tregs in a variety of disease settings and the mechanisms they utilize for suppression.


Assuntos
Linfócitos T Reguladores/imunologia , Animais , Diferenciação Celular , Citocinas/fisiologia , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Fatores de Transcrição Forkhead/fisiologia , Humanos , Tolerância Imunológica , Imunidade Celular , Camundongos , Modelos Imunológicos , Receptores de Antígenos de Linfócitos T/fisiologia , Linfócitos T Reguladores/citologia
13.
Mol Immunol ; 44(7): 1691-703, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16997376

RESUMO

Workshop cluster 1(+) gamma delta (WC1(+)gammadelta) T cells have been shown to play important roles in the immune response to infections. WC1 is a transmembrane glycoprotein, uniquely expressed on the surface of gammadelta T cells of ruminants and pigs. A role for WC1 in inducing a reversible growth arrest of gammadelta T cells has been previously demonstrated. WC1-induced growth inhibition has been shown to be overcome following gammadelta T cell activation with Concanavalin A (Con A). However, molecular mechanism(s) by which WC1 signalling might be modulated following activation have not been elucidated. In this paper we show that Con A activation of bovine lymphocytes induces the tyrosine phosphorylation of WC1 in a Src-family kinase-dependent manner. Src family kinases also phosphorylated WC1 in a COS-7 co-transfection system. Furthermore, a glutathione-S-transferase (GST)-WC1 cytoplasmic domain fusion protein was directly phosphorylated by recombinant Lck (rLck) in vitro. The Y(1303) of WC1 was identified by mutational analysis as the only one of the five WC1 tyrosine residues to be critical for Src family phosphorylation. The importance of activation-induced Src family activity for WC1 function was investigated with the Src-family specific inhibitor PP2. These studies show that the surface levels of WC1 are down regulated in a Src-family-dependent manner following activation of bovine lymphocytes. Down regulation of surface WC1 was accompanied by a Src-family-dependent accumulation of intracellular WC1. These data show that WC1 is modulated by activation-induced tyrosine phosphorylation thus providing a new insight into the signalling mechanisms by which WC1 and gammadelta T cell activation are regulated in this important and unique cell population.


Assuntos
Glicoproteínas de Membrana/metabolismo , Linfócitos T/imunologia , Quinases da Família src/metabolismo , Sequência de Aminoácidos , Animais , Células COS , Bovinos , Chlorocebus aethiops , Concanavalina A/farmacologia , Análise Mutacional de DNA , Regulação para Baixo , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Glicoproteínas de Membrana/análise , Glicoproteínas de Membrana/genética , Dados de Sequência Molecular , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Receptores de Antígenos de Linfócitos T gama-delta/análise , Linfócitos T/química , Linfócitos T/efeitos dos fármacos , Tirosina/química , Tirosina/genética , Tirosina/metabolismo , Quinases da Família src/antagonistas & inibidores
14.
Cancer Res ; 64(20): 7370-6, 2004 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-15492258

RESUMO

Aneuploidy and chromosome instability are common abnormalities in human cancer. Loss of control over mitotic progression, multipolar spindle formation, and cytokinesis defects are all likely to contribute to these phenotypes. Nek2 is a cell cycle-regulated protein kinase with maximal activity at the onset of mitosis that localizes to the centrosome. Functional studies have implicated Nek2 in regulation of centrosome separation and spindle formation. Here, we present the first study of the protein expression levels of the Nek2 kinase in human cancer cell lines and primary tumors. Nek2 protein is elevated 2- to 5-fold in cell lines derived from a range of human tumors including those of cervical, ovarian, breast, prostate, and leukemic origin. Most importantly, by immunohistochemistry, we find that Nek2 protein is significantly up-regulated in preinvasive in situ ductal carcinomas of the breast as well as in invasive breast carcinomas. Finally, by ectopic expression of Nek2A in immortalized HBL100 breast epithelial cells, we show that increased Nek2 protein leads to accumulation of multinucleated cells with supernumerary centrosomes. These data highlight the Nek2 kinase as novel potential target for chemotherapeutic intervention in breast cancer.


Assuntos
Neoplasias da Mama/enzimologia , Proteínas Serina-Treonina Quinases/biossíntese , Aneuploidia , Mama/metabolismo , Mama/fisiologia , Neoplasias da Mama/genética , Carcinoma in Situ/enzimologia , Carcinoma in Situ/genética , Carcinoma Ductal/enzimologia , Carcinoma Ductal/genética , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Humanos , Imuno-Histoquímica , Quinases Relacionadas a NIMA , Proteínas Serina-Treonina Quinases/genética , Transfecção , Regulação para Cima
15.
Dev Biol ; 265(2): 384-98, 2004 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-14732400

RESUMO

Pronuclear migration and formation of the first mitotic spindle depend upon assembly of a functional zygotic centrosome. For most animals, this involves both paternal and maternal contributions as sperm basal bodies are converted into centrosomes competent for microtubule nucleation through recruitment of egg proteins. Nek2B is a vertebrate NIMA-related protein kinase required for centrosome assembly, as its depletion from egg extracts delays microtubule aster formation from sperm basal bodies. Using Xenopus as a model system, we now show that protein expression of Nek2B begins during mid-oogenesis and increases further upon oocyte maturation. This is regulated, at least in part, at the level of protein translation. Nek2B protein is weakly phosphorylated in mitotic egg extracts but its recruitment to the sperm basal body, which occurs independently of its kinase activity, stimulates its phosphorylation, possibly through sequestration from a phosphatase present in mitotic egg cytoplasm. Importantly, although Nek2B is not required to organize acentrosomal microtubule asters, we show that addition of either active or kinase-dead recombinant Nek2B can restore centrosome assembly in a dose-dependent manner to a depleted extract. These results support a model in which maternal Nek2B acts to promote assembly of a functional zygotic centrosome in a kinase-independent manner.


Assuntos
Centrossomo/enzimologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas de Xenopus , Zigoto/enzimologia , Animais , Centrossomo/metabolismo , Citoplasma/enzimologia , Feminino , Isoenzimas/metabolismo , Masculino , Microtúbulos/enzimologia , Oócitos/enzimologia , Oogênese/fisiologia , Óvulo/enzimologia , Espermatozoides/enzimologia , Xenopus laevis , Zigoto/metabolismo
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