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1.
Mol Vis ; 17: 989-96, 2011 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-21541273

RESUMO

PURPOSE: The aim of our work was to study apoptosis during the development of the retinal pigment epithelium (RPE) in mice between embryonic day (E) 10.5 and E12.5 and to examine a possible link between apoptosis and pigmentation. METHODS: We collected mouse embryos at E10.5, E11.5, and E12.5 and labeled apoptotic cells in 5-µm paraffin sections, using the terminal deoxynucleotidyl transferase dUTP nick end labeling technique. We counted the total number of cells and the number of apoptotic cells in the early developing RPE and calculated the percentage of apoptosis at each stage. RESULTS: In the C57BL/6J mouse, 17% of the RPE cells were apoptotic at E10.5 compared to 0.9% at E12.5. At E11.5, three-quarters of the RPE cells began to pigment, and apoptotic cells were located mostly in the nonpigmented part. In contrast, in the BALB/c mouse (tyrosinase-deficient) and pJ mouse (carrying mutations in the p gene) hypopigmented strains, the RPE contained significantly fewer apoptotic cells (7.5% and 10.1%, respectively) at E10.5 than controls. Subsequently at E11.5 and E12.5, the two hypopigmented strains displayed different apoptotic patterns; the BALB/c RPE had a similar percentage of apoptotic cells to controls (1.5% and 1.1%, respectively, for BALB/c versus 3.0% and 0.9%, respectively, for C57BL/6J), whereas the pJ RPE contained significantly more apoptosis (7.5% and 3.5%, respectively). Overall we observed differences in the evolution of the relative total number of RPE cells between the three strains. CONCLUSIONS: Apoptosis is a main event during the first stages of normal RPE development, indicating an essential role during RPE differentiation. Moreover, the early apoptotic pattern and possibly the whole early development of the RPE is different between hypopigmented and pigmented strains, as well as between BALB/c and pJ mice. This suggests the existence of regulatory and developmental differences with a more complex origin than just differing pigmentation levels.


Assuntos
Embrião de Mamíferos/citologia , Epitélio Pigmentado da Retina , Albinismo/genética , Substituição de Aminoácidos/genética , Animais , Apoptose , Diferenciação Celular , Embrião de Mamíferos/metabolismo , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Monofenol Mono-Oxigenase/genética , Monofenol Mono-Oxigenase/metabolismo , Pigmentação/genética , Epitélio Pigmentado da Retina/citologia , Epitélio Pigmentado da Retina/embriologia , Especificidade da Espécie
3.
Dev Dyn ; 228(2): 231-8, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-14517994

RESUMO

Apoptosis plays a major role in the development of the central nervous system. Previous studies of apoptosis induction during retinal development are difficult to interpret, however, because they explored different mouse strains, different developmental periods, and used different assays. Here, we first established a comprehensive sequential pattern of cell death during the whole development of the C57BL/6J mouse retina, from E10.5 to postnatal day (P) 21 by using the terminal deoxynucleotidyl transferase (TdT) -mediated deoxyuridine triphosphate (dUTP)-biotinylated nick end labeling (TUNEL) assay. We confirmed the existence of three previously described apoptotic peaks and identified another, later peak at P15, in both the outer nuclear layer, in which the photoreceptors differentiate, and the ganglion cell layer. Comparison of wild-type C57BL/6 mice, gld mice, defective in the death ligand fasL, and bax-/- mice, defective in the pro-apoptotic BAX protein, revealed a minor role for FAS ligand but a crucial role for BAX in both apoptosis and normal retinal development. The lack of BAX resulted in thicker than normal inner neuroblastic and ganglion cell layers in adults, with larger numbers of cells and an impaired electroretinogram response related to a decreased number of responsive cells. Our findings indicate that cell death during normal retinal development is important for the modeling of a functional vision organ and showed that the pro-apoptotic BAX protein plays a crucial role in this process.


Assuntos
Apoptose , Proteínas Proto-Oncogênicas c-bcl-2 , Proteínas Proto-Oncogênicas/metabolismo , Retina/embriologia , Retina/fisiologia , Visão Ocular , Animais , Diferenciação Celular , Eletrorretinografia , Dosagem de Genes , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Knockout , Proteínas Proto-Oncogênicas/genética , Retina/citologia , Fatores de Tempo , Proteína X Associada a bcl-2 , Receptor fas/fisiologia
4.
Hum Mutat ; 17(5): 374-81, 2001 May.
Artigo em Inglês | MEDLINE | ID: mdl-11317352

RESUMO

Cytochrome c oxidase (COX) deficiency is one of the major causes of Leigh Syndrome (LS), a fatal encephalopathy of infancy or childhood, characterized by symmetrical lesions in the basal ganglia and brainstem. Mutations in the nuclear genes encoding COX subunits have not been found in patients with LS and COX deficiency, but mutations have been identified in SURF1. SURF1 encodes a factor involved in COX biogenesis. To date, 30 different mutations have been reported in 40 unrelated patients. We aim to provide an overview of all known mutations in SURF1, and to propose a common nomenclature. Twelve of the mutations were insertion/deletion mutations in exons 1, 4, 6, 8, and 9; 10 were missense/nonsense mutations in exons 2, 4, 5, 7, and 8; and eight were detected at splicing sites in introns 3 to 7. The most frequent mutation was 312_321del 311_312insAT which was found in 12 patients out of 40. Twenty mutations have been described only once. We also list all polymorphisms discovered to date.


Assuntos
Deficiência de Citocromo-c Oxidase , Doença de Leigh/genética , Mutação/genética , Proteínas/genética , Terminologia como Assunto , Sequência de Aminoácidos , Sequência de Bases , Análise Mutacional de DNA , Complexo IV da Cadeia de Transporte de Elétrons/genética , Éxons/genética , Frequência do Gene , Testes Genéticos , Humanos , Íntrons/genética , Doença de Leigh/diagnóstico , Doença de Leigh/enzimologia , Proteínas de Membrana , Proteínas Mitocondriais , Dados de Sequência Molecular , Polimorfismo Genético/genética , Proteínas/química , Sítios de Splice de RNA/genética
5.
J Biol Chem ; 276(18): 15326-9, 2001 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-11279059

RESUMO

The gene SURF1 encodes a factor involved in the biogenesis of cytochrome c oxidase, the last complex in the respiratory chain. Mutations of the SURF1 gene result in Leigh syndrome and severe cytochrome c oxidase deficiency. Analysis of seven unrelated patients with cytochrome c oxidase deficiency and typical Leigh syndrome revealed different SURF1 mutations in four of them. Only these four cases had associated demyelinating neuropathy. Three mutations were novel splicing-site mutations that lead to the excision of exon 6. Two different novel heterozygous mutations were found at the same guanine residue at the donor splice site of intron 6; one was a deletion, whereas the other was a transition [588+1G>A]. The third novel splicing-site mutation was a homozygous [516-2_516-1delAG] in intron 5. One patient only had a homozygous polymorphism in the middle of the intron 8 [835+25C>T]. Western blot analysis showed that Surf1 protein was absent in all four patients harboring mutations. Our studies confirm that the SURF1 gene is an important nuclear gene involved in the cytochrome c oxidase deficiency. We also show that Surf1 protein is not implicated in the assembly of other respiratory chain complexes or the pyruvate dehydrogenase complex.


Assuntos
Doença de Leigh/genética , Mutação , Proteínas/genética , Splicing de RNA , Sequência de Bases , Primers do DNA , Feminino , Heterozigoto , Homozigoto , Humanos , Lactente , Masculino , Proteínas de Membrana , Proteínas Mitocondriais
6.
Neurobiol Dis ; 7(6 Pt B): 586-99, 2000 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11114258

RESUMO

The RCS rat presents an autosomal recessive retinal pigment epithelium dystrophy characterized by the outer segments of photoreceptors being phagocytosis-deficient. A systematic genetic study allowed us to restrict the interval containing the rdy locus to that between the markers D3Mit13 and D3Rat256. We report the chromosomal localization of the rat c-mer gene in the cytogenetic bands 3q35-36, based on genetic analysis and radiation hybrid mapping. Using a systematic biocomputing analysis, we identified two strong related candidate genes encoding protein tyrosine kinase receptors of the AXL subfamily. The comparison of their expression patterns in human and mice tissues suggested that the c-mer gene was the best gene to screen for mutations. RCS rdy- and RCS rdy+ cDNAs were sequenced. The RCS rdy- cDNAs carried a significant deletion in the 5' part of the coding sequence of the c-mer gene resulting in a shortened aberrant transcript encoding a 20 amino acid peptide. The c-mer gene contains characteristic motifs of neural cell adhesion. A ligand of the c-mer receptor, Gas6, exhibits antiapoptotic properties.


Assuntos
Homozigoto , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases , Doenças Retinianas/genética , Deleção de Sequência/genética , Sequência de Aminoácidos , Animais , Apoptose/genética , Sequência de Bases , Adesão Celular/genética , Mapeamento Cromossômico , Cruzamentos Genéticos , Eletrorretinografia , Angiofluoresceinografia , Genes Recessivos , Genótipo , Endogamia , Dados de Sequência Molecular , Especificidade de Órgãos/genética , Fenótipo , RNA Mensageiro/genética , Ratos , Ratos Endogâmicos BN , Ratos Mutantes , Doenças Retinianas/etiologia , Análise de Sequência de DNA , c-Mer Tirosina Quinase
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