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1.
Nature ; 434(7036): 1031-5, 2005 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-15846349

RESUMO

Sensory hair cells and their associated non-sensory supporting cells in the inner ear are fundamental for hearing and balance. They arise from a common progenitor, but little is known about the molecular events specifying this cell lineage. We recently identified two allelic mouse mutants, light coat and circling (Lcc) and yellow submarine (Ysb), that show hearing and balance impairment. Lcc/Lcc mice are completely deaf, whereas Ysb/Ysb mice are severely hearing impaired. We report here that inner ears of Lcc/Lcc mice fail to establish a prosensory domain and neither hair cells nor supporting cells differentiate, resulting in a severe inner ear malformation, whereas the sensory epithelium of Ysb/Ysb mice shows abnormal development with disorganized and fewer hair cells. These phenotypes are due to the absence (in Lcc mutants) or reduced expression (in Ysb mutants) of the transcription factor SOX2, specifically within the developing inner ear. SOX2 continues to be expressed in the inner ears of mice lacking Math1 (also known as Atoh1 and HATH1), a gene essential for hair cell differentiation, whereas Math1 expression is absent in Lcc mutants, suggesting that Sox2 acts upstream of Math1.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Orelha Interna/embriologia , Orelha Interna/metabolismo , Transativadores/metabolismo , Alelos , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Diferenciação Celular , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Orelha Interna/anormalidades , Orelha Interna/patologia , Células Ciliadas Auditivas Internas/anormalidades , Células Ciliadas Auditivas Internas/metabolismo , Células Ciliadas Auditivas Internas/patologia , Camundongos , Camundongos Mutantes , Mutação/genética , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Transcrição SOXB1 , Transativadores/deficiência , Transativadores/genética , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
2.
Reprod Biomed Online ; 13(1): 88-95, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16820117

RESUMO

Meiotic recombination was analysed in human fetal oocytes to determine whether recombination errors are associated with abnormal chromosome synapsis. Immunostaining was used to identify the synaptonemal complex (SC, the meiosis-specific proteinaceous structure that binds homologous chromosomes) and the DNA mismatch repair protein, MLH1, that locates recombination foci. It was found that 57.1-74.2% of zygotene oocytes showed fragmentation and/or defective chromosome synapsis. Fewer such abnormal cells occurred at pachytene (15.8-28.9%). MLH1 foci were present from zygotene to diplotene in both normal and abnormal oocytes. However, the proportions of oocytes having MLH1 foci, and mean numbers of foci per oocyte, were both lower in abnormal oocytes. Oocytes with fragmented SC had more foci than those with synaptic anomalies. Analysis of chromosomes 13, 18, 21 and X by fluorescence in-situ hybridization (FISH) did not implicate particular chromosomes in recombination deficiency. These observations indicate that recombination is disturbed in oocytes with SC fragmentation and/or synaptic abnormalities during meiotic prophase I. Such disturbances might be a risk factor for selection of fetal oocytes for atresia, as occurs for homologous chromosome pairing. Recombination errors may potentially increase the risk of abnormal chromosome segregation in oocytes that survive and contribute to the reserve in the mature ovary.


Assuntos
Feto/citologia , Meiose , Oócitos/citologia , Proteínas Adaptadoras de Transdução de Sinal , Proteínas de Transporte/metabolismo , Feminino , Feto/metabolismo , Humanos , Hibridização in Situ Fluorescente , Técnicas In Vitro , Proteína 1 Homóloga a MutL , Proteínas Nucleares/metabolismo , Oócitos/metabolismo , Recombinação Genética , Complexo Sinaptonêmico/ultraestrutura
3.
Am J Hum Genet ; 70(6): 1469-79, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-11992253

RESUMO

Abnormal patterns of meiotic recombination (i.e., crossing-over) are believed to increase the risk of chromosome nondisjunction in human oocytes. To date, information on recombination has been obtained using indirect, genetic methods. Here we use an immunocytological approach, based on detection of foci of a DNA mismatch-repair protein, MLH1, on synaptonemal complexes at prophase I of meiosis, to provide the first direct estimate of the frequency of meiotic recombination in human oocytes. At pachytene, the stage of maximum homologous chromosome pairing, we found a mean of 70.3 foci (i.e., crossovers) per oocyte, with considerable intercell variability (range 48-102 foci). This mean equates to a genetic-map length of 3,515 cM. The numbers and positions of foci were determined for chromosomes 21, 18, 13, and X. These chromosomes yielded means of 1.23 foci (61.5 cM), 2.36 foci (118 cM), 2.5 foci (125 cM), and 3.22 foci (161 cM), respectively. The foci were almost invariably located interstitially and were only occasionally located close to chromosome ends. These data confirm the large difference, in recombination frequency, between human oocytes and spermatocytes and demonstrate a clear intersex variation in distribution of crossovers. In a few cells, chromosomes 21 and 18 did not have any foci (i.e., were presumptively noncrossover); however, configurations that lacked foci were not observed for chromosomes 13 and X. For the latter two chromosome pairs, the only instances of absence of foci were observed in abnormal cells that showed chromosome-pairing errors affecting these chromosomes. We speculate that these abnormal fetal oocytes may be the source of the nonrecombinant chromosomes 13 and X suggested, by genetic studies, to be associated with maternally derived chromosome nondisjunction.


Assuntos
Cromossomos Humanos/genética , Feto/citologia , Meiose/genética , Oócitos/citologia , Oócitos/metabolismo , Recombinação Genética/genética , Proteínas Adaptadoras de Transdução de Sinal , Proteínas de Transporte , Pareamento Cromossômico/genética , Segregação de Cromossomos/genética , Cromossomos Humanos/metabolismo , Troca Genética/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Proteína 1 Homóloga a MutL , Proteínas de Neoplasias/metabolismo , Não Disjunção Genética , Proteínas Nucleares , Espermatócitos/citologia , Espermatócitos/metabolismo , Complexo Sinaptonêmico/metabolismo
4.
Chromosome Res ; 12(3): 197-213, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15125634

RESUMO

Cohesins are chromosomal proteins that form complexes involved in the maintenance of sister chromatid cohesion during division of somatic and germ cells. Three meiosis-specific cohesin subunits have been reported in mammals, REC8, STAG3 and SMC1 beta; their expression in mouse spermatocytes has also been described. Here we studied the localization of different meiotic and mitotic cohesin components during prophase I in human and murine female germ cells. In normal and atretic human fetal oocytes, from leptotene to diplotene stages, REC8 and STAG3 colocalize in fibers. In murine oocytes, SMC1beta, SMC3 and STAG3 are localized along fibers that correspond first to the chromosome axis and then to the synaptonemal complex in pachytene. Mitotic cohesin subunit RAD21 is also found in fibers that decorate the SC during prophase I in mouse oocytes, suggesting a role for this cohesin in mammalian sister chromatid cohesion in female meiosis. We observed that, unlike human oocytes, murine synaptonemal complex protein SYCP3 localizes to nucleoli throughout prophase I stages, and centromeres cluster in discrete locations from leptotene to dictyate. At difference from meiosis in male mice, the cohesin axis is progressively lost during the first week after birth in females with a parallel destruction of the axial elements at dictyate arrest, demonstrating sexual dimorphism in sister chromatid cohesion in meiosis.


Assuntos
Proteínas Nucleares/análise , Oócitos/química , Animais , Anticorpos/imunologia , Proteínas de Ciclo Celular/imunologia , Proteínas de Ciclo Celular/metabolismo , Centrômero/metabolismo , Proteoglicanas de Sulfatos de Condroitina/imunologia , Proteoglicanas de Sulfatos de Condroitina/metabolismo , Cromátides/metabolismo , Proteínas Cromossômicas não Histona/imunologia , Proteínas Cromossômicas não Histona/metabolismo , Proteínas de Ligação a DNA , Feminino , Imunofluorescência , Proteínas Fúngicas , Humanos , Meiose , Camundongos , Proteínas Nucleares/imunologia , Proteínas Nucleares/metabolismo , Oócitos/citologia , Oócitos/metabolismo , Fosfoproteínas/imunologia , Fosfoproteínas/metabolismo , Prófase , Coesinas
5.
Genomics ; 79(6): 777-84, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12036291

RESUMO

We describe here two mouse mutants, yellow submarine (Ysb) and light coat and circling (Lcc). Ysb arose as the result of insertions of a transgene, pAA2, into the genome. Lcc is an independent, radiation-induced mutation. Both mutants are characterized by recessive circling behavior and deafness, associated with a non-segregating, semi-dominant yellow coat color. Complementation tests showed that Ysb and Lcc are allelic. We attribute the yellow coat in Ysb and Lcc mice to the absence of black awl overhairs, increased agouti zigzag underhairs, and the presence of agouti awls with long subapical yellow pigment. Chromosomal mapping and genomic characterization showed the Ysb and Lcc mutations involve complex chromosomal rearrangements in overlapping regions of mouse chromosome 3, A2/A3-B/C and B-E1, respectively. Ysb and Lcc show for the first time, to our knowledge, the presence of genes in the B-C region of chromosome 3 important for balance and hearing and the pigmentation and specification of coat hair.


Assuntos
Surdez/genética , Mutação , Pigmentação/genética , Animais , Camundongos , Camundongos Transgênicos , Mutação/efeitos da radiação , Pigmentação/efeitos da radiação , Equilíbrio Postural/fisiologia , Equilíbrio Postural/efeitos da radiação , Comportamento Estereotipado/efeitos da radiação
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