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1.
Development ; 141(4): 855-66, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24496622

RESUMO

Outbred XY(Sry-) female mice that lack Sry due to the 11 kb deletion Sry(dl1Rlb) have very limited fertility. However, five lines of outbred XY(d) females with Y chromosome deletions Y(Del(Y)1Ct)-Y(Del(Y)5Ct) that deplete the Rbmy gene cluster and repress Sry transcription were found to be of good fertility. Here we tested our expectation that the difference in fertility between XO, XY(d-1) and XY(Sry-) females would be reflected in different degrees of oocyte depletion, but this was not the case. Transgenic addition of Yp genes to XO females implicated Zfy2 as being responsible for the deleterious Y chromosomal effect on fertility. Zfy2 transcript levels were reduced in ovaries of XY(d-1) compared with XY(Sry-) females in keeping with their differing fertility. In seeking the biological basis of the impaired fertility we found that XY(Sry-), XY(d-1) and XO,Zfy2 females produce equivalent numbers of 2-cell embryos. However, in XY(Sry-) and XO,Zfy2 females the majority of embryos arrested with 2-4 cells and almost no blastocysts were produced; by contrast, XY(d-1) females produced substantially more blastocysts but fewer than XO controls. As previously documented for C57BL/6 inbred XY females, outbred XY(Sry-) and XO,Zfy2 females showed frequent failure of the second meiotic division, although this did not prevent the first cleavage. Oocyte transcriptome analysis revealed major transcriptional changes resulting from the Zfy2 transgene addition. We conclude that Zfy2-induced transcriptional changes in oocytes are sufficient to explain the more severe fertility impairment of XY as compared with XO females.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Infertilidade Feminina/genética , Meiose/genética , Oócitos/metabolismo , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/genética , Proteína da Região Y Determinante do Sexo/deficiência , Fatores de Transcrição/metabolismo , Cromossomo Y/genética , Animais , Western Blotting , Cruzamento , Fase de Clivagem do Zigoto/patologia , Fase de Clivagem do Zigoto/fisiologia , Cruzamentos Genéticos , Proteínas de Ligação a DNA/genética , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/genética , Genótipo , Modelos Lineares , Camundongos , Camundongos Transgênicos , Análise em Microsséries , Fatores de Transcrição/genética
2.
Antiviral Res ; 200: 105281, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35292289

RESUMO

Global analysis of the susceptibility of influenza viruses to neuraminidase (NA) inhibitors (NAIs) and the polymerase acidic (PA) inhibitor (PAI) baloxavir was conducted by five World Health Organization Collaborating Centres for Reference and Research on Influenza during two periods (May 2018-May 2019 and May 2019-May 2020). Combined phenotypic and NA sequence-based analysis revealed that the global frequency of viruses displaying reduced or highly reduced inhibition (RI or HRI) or potential to show RI/HRI by NAIs remained low, 0.5% (165/35045) and 0.6% (159/26010) for the 2018-2019 and 2019-2020 periods, respectively. The most common amino acid substitution was NA-H275Y (N1 numbering) conferring HRI by oseltamivir and peramivir in A(H1N1)pdm09 viruses. Combined phenotypic and PA sequence-based analysis showed that the global frequency of viruses showing reduced susceptibility to baloxavir or carrying substitutions associated with reduced susceptibility was low, 0.5% (72/15906) and 0.1% (18/15692) for the 2018-2019 and 2019-2020 periods, respectively. Most (n = 61) of these viruses had I38→T/F/M/S/L/V PA amino acid substitutions. In Japan, where baloxavir use was highest, the rate was 4.5% (41/919) in the 2018-2019 period and most of the viruses (n = 32) had PA-I38T. Zoonotic viruses isolated from humans (n = 32) in different countries did not contain substitutions in NA associated with NAI RI/HRI phenotypes. One A(H5N6) virus had a dual substitution PA-I38V + PA-E199G, which may reduce susceptibility to baloxavir. Therefore, NAIs and baloxavir remain appropriate choices for the treatment of influenza virus infections, but close monitoring of antiviral susceptibility is warranted.


Assuntos
Vírus da Influenza A Subtipo H1N1 , Influenza Humana , Substituição de Aminoácidos , Antivirais/farmacologia , Antivirais/uso terapêutico , Dibenzotiepinas , Farmacorresistência Viral/genética , Endonucleases/genética , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza B , Morfolinas , Neuraminidase/genética , Neuraminidase/uso terapêutico , Oseltamivir/farmacologia , Oseltamivir/uso terapêutico , Piridonas , Triazinas
3.
Genetics ; 166(2): 901-12, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15020475

RESUMO

The mouse Y chromosome carries 10 distinct genes or gene families that have open reading frames suggestive of retained functionality; it has been assumed that many of these function in spermatogenesis. However, we have recently shown that only two Y genes, the testis determinant Sry and the translation initiation factor Eif2s3y, are essential for spermatogenesis to proceed to the round spermatid stage. Thus, any further substantive mouse Y-gene functions in spermatogenesis are likely to be during sperm differentiation. The complex Ssty gene family present on the mouse Y long arm (Yq) has been implicated in sperm development, with partial Yq deletions that reduce Ssty expression resulting in impaired fertilization efficiency. Here we report the identification of a more extensive Yq deletion that abolishes Ssty expression and results in severe sperm defects and sterility. This result establishes that genetic information (Ssty?) essential for normal sperm differentiation and function is present on mouse Yq.


Assuntos
Deleção Cromossômica , Infertilidade Masculina/genética , Proteínas/genética , Espermatozoides/anormalidades , Cromossomo Y/genética , Animais , Infertilidade Masculina/etiologia , Masculino , Camundongos , Proteínas Nucleares , Proteínas/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo
4.
Mol Biol Cell ; 21(20): 3497-505, 2010 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-20739462

RESUMO

The human and mouse sex chromosomes are enriched in multicopy genes required for postmeiotic differentiation of round spermatids into sperm. The gene Sly is present in multiple copies on the mouse Y chromosome and encodes a protein that is required for the epigenetic regulation of postmeiotic sex chromosome expression. The X chromosome carries two multicopy genes related to Sly: Slx and Slxl1. Here we investigate the role of Slx/Slxl1 using transgenically-delivered small interfering RNAs to disrupt their function. We show that Slx and Slxl1 are important for normal sperm differentiation and male fertility. Slx/Slxl1 deficiency leads to delay in spermatid elongation and sperm release. A high proportion of delayed spermatids are eliminated via apoptosis, with a consequent reduced sperm count. The remaining spermatozoa are abnormal with impaired motility and fertilizing abilities. Microarray analyses reveal that Slx/Slxl1 deficiency affects the metabolic processes occurring in the spermatid cytoplasm but does not lead to a global perturbation of sex chromosome expression; this is in contrast with the effect of Sly deficiency which leads to an up-regulation of X and Y chromosome genes. This difference may be due to the fact that SLX/SLXL1 are cytoplasmic while SLY is found in the nucleus and cytoplasm of spermatids.


Assuntos
Dosagem de Genes/genética , Proteínas Nucleares/deficiência , Espermátides/patologia , Espermatogênese/genética , Animais , Apoptose , Fertilidade/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Masculino , Camundongos , Camundongos Transgênicos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Cromossomos Sexuais/genética , Contagem de Espermatozoides , Motilidade dos Espermatozoides , Espermátides/metabolismo , Espermátides/ultraestrutura , Testículo/metabolismo , Testículo/patologia
5.
Biol Reprod ; 69(2): 483-8, 2003 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12700203

RESUMO

Mice of the XO genotype with a paternally derived X chromosome (XpO) have placental hyperplasia in late pregnancy, although in early pregnancy the ectoplacental cone, a placental precursor, is smaller in XpO mice than in their XX sibs. This early size deficiency of the ectoplacental cone is apparently a consequence of Xp imprinting, because XmO embryos (with a maternally derived X chromosome) are unaffected. In the present study we sought to establish whether XpO placental hyperplasia in late pregnancy is also a consequence of Xp imprinting. Placental weight data were first collected from litters that included XpO or XmO fetuses and XX controls. Comparison of XO placentae with XX placentae showed that XpO and XmO placentae are hyperplastic. This finding suggested that the hyperplasia might be an X dosage effect, and this hypothesis was supported by the finding that XY male fetuses from the same crosses also had larger placentae than their XX sibs. Further analysis of a range of sex-chromosome variant genotypes, including XmYSry-negative females and XXSry transgenic males, showed that mouse fetuses with one X chromosome consistently had larger placentae than littermates with two X chromosomes, independent of their gonadal/androgen status.


Assuntos
Dosagem de Genes , Placenta/anatomia & histologia , Cromossomos Sexuais/genética , Animais , Peso Corporal/fisiologia , Embrião de Mamíferos/fisiologia , Desenvolvimento Embrionário e Fetal/fisiologia , Feminino , Genótipo , Masculino , Camundongos , Tamanho do Órgão/fisiologia , Gravidez , Cromossomo X/genética , Cromossomo Y/genética
6.
Genomics ; 83(1): 140-7, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-14667817

RESUMO

Multicopy Y-chromosomal genes in human and mouse have been postulated to play a role in spermatogenesis. The mouse Y long arm (Yq) carries hundreds of supposedly intronless copies of Ssty, for which no protein has hitherto been identified; mice lacking Yq are sterile with grossly abnormal sperm. We have now identified an Ssty-encoded protein (Ssty1) that is expressed in spermatids. The protein is absent from spermatids of mice that lack Yq, but is not reduced in mice with a two-thirds reduction of Ssty copies, implying that most do not produce this protein. Furthermore, no protein was produced by a strongly transcribed intronless Ssty transgene, raising doubts as to the protein-encoding potential of these intronless genes. We have now identified an intron-containing copy that is also present in multiple copies on Yq. One or more intron-containing copies are retained in the Ssty-deficient mice and may be the source of the Ssty1 protein.


Assuntos
Família Multigênica/genética , Proteínas/genética , Espermatogênese/genética , Cromossomo Y/genética , Sequência de Aminoácidos , Animais , Afinidade de Anticorpos , Sequência de Bases , Western Blotting , DNA Complementar/química , DNA Complementar/genética , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Íntrons/genética , Masculino , Camundongos , Dados de Sequência Molecular , Proteínas/imunologia , Proteínas/metabolismo , Análise de Sequência de DNA , Homologia de Sequência de Aminoácidos , Espermátides/metabolismo
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