Mlh1 Deficiency in Zebrafish Results in Male Sterility and Aneuploid as Well as Triploid Progeny in Females

Defective mismatch repair (MMR) in humans causes hereditary nonpolyposis colorectal cancer. This genetic predisposition to colon cancer is linked to heterozygous familial mutations, and loss-of-heterozygosity is necessary for tumor development. In contrast, the rare cases with biallelic MMR mutations are juvenile patients with brain tumors, skin neurofibromas, and café-au-lait spots, resembling the neurofibromatosis syndrome. Many of them also display lymphomas and leukemias, which phenotypically resembles the frequent lymphoma development in mouse MMR knockouts. Here, we describe the identification and characterization of novel knockout mutants of the three major MMR genes, mlh1, msh2, and msh6, in zebrafish and show that they develop tumors at low frequencies. Predominantly, neurofibromas/ malignant peripheral nerve sheath tumors were observed; however, a range of other tumor types was also observed. Our findings indicate that zebrafish mimic distinct features of the human disease and are complementary to mouse models. [Cancer Res 2008;68(13):5059-66]

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“…1A and D). We recently showed that this mutation results in full loss-of-function of MLH1 and causes a strong meiotic phenotype (35).…”

Section: Resultsmentioning

confidence: 99%

“…Genotyping was done either by PCR amplification and resequencing or by using KASPAR genotyping technology (Kbioscience). The mlh1 (hu1919) mutants were generated as described previously (35).…”

Section: Pcrmentioning

confidence: 99%

Zebrafish with Mutations in Mismatch Repair Genes Develop Neurofibromas and Other Tumors

et al. 2008

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“…Morphometric analysis of testis of control and E 2 -exposed fish was conducted according to Feitsma et al (2007) with some modifications. Volume fractions of various testicular tissue components were determined as the area of cysts containing cells normalized by the total area of testis analysed to obtain a percentage of total tissue for each component.…”

Section: Histologymentioning

confidence: 99%

Cyp17a1 and Cyp19a1 in the zebrafish testis are differentially affected by oestradiol

Hinfray¹,

Nóbrega²,

Caulier³

et al. 2013

Journal of Endocrinology

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International audienceOestrogens can affect expression of genes encoding steroidogenic enzymes in fish gonads. However, little information is available on their effects at the protein level. In this context, we first analysed the expression of key steroidogenic enzyme genes and proteins in zebrafish testis, paying attention also to other cell types than Leydig cells. Gene expression was analysed by quantitative PCR on fluorescence-activated cell-sorting fractions coupled or not to differential plating, while protein synthesis was studied by immunohistochemistry using specific antibodies against zebrafish Cyp17a1, Cyp19a1a and Cyp19a1b. Furthermore, we have evaluated the effect of oestrogen treatment (17 beta-oestradiol (E-2), 10 nM) on the localization of these enzymes after 7 and 14 days of in vivo exposure in order to study how oestrogen-mediated modulation of their expression is linked to oestrogen effects on spermatogenesis. The major outcomes of this study are that Leydig cells express Cyp17a1 and Cyp19a1a, while testicular germ cells express Cyp17a1 and both, Cyp19a1a and Cyp19a1b. As regards Cyp17a1, both protein and mRNA seem to be quantitatively dominating in Leydig cells. Moreover, E-2 exposure specifically affects only Leydig cell Cyp17a1 synthesis, preceding the disruption of spermatogenesis. The oestrogen-induced suppression of the androgen production capacity in Leydig cells is a major event in altering spermatogenesis, while germ cell steroidogenesis may have to be fuelled by precursors from Leydig cells. Further studies are needed to elucidate the functionality of steroidogenic enzymes in germ cells and their potential role in testicular physiology

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“…In zebrafish, MLH1 mutants fail to form chiasmata and display univalents in metaphase I resulting in arrest of spermatogenesis and subsequent infertility. Females produce aneuploid gametes, an indication of chromosomal missegregation (Feitsma et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Sex-specific crossover patterns in Zebrafish (Danio rerio)

Kochakpour

Møens

2008

Heredity

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Some species display intersex variation in their rate of meiotic recombination, where recombination is usually suppressed in the heterogametic sex. Although no heteromorphic sex chromosomes have been detected in zebrafish (Danio rerio), genetic analysis has indicated a lower frequency of recombination in males relative to females. Our study of the meiotic recombination pattern in female zebrafish indicates that adult females have only a few meiotic oocytes that are found in groups in the ventral zone of the ovarian surface. We used antibody staining of human mutL homolog 1 (MLH1) protein to mark the sites of putative chiasmata to seek a physical basis for the pattern of recombination and its relative frequency in both sexes. We report that MLH1 foci are found mostly in distal regions of the synaptonemal complexes (SCs) in males, but tend to be more evenly distributed in females.Our cytological analysis yields a ratio of MLH1 foci per chromosome in males versus females of 1:1.55. This lower level of recombination in males is in general agreement with previously published results from linkage map analysis. However, the similar ratio of MLH1 foci per unit length of SCs in both sexes demonstrates a correlation between SC length and the frequency of recombination rather than a mechanism that suppresses recombination in males. Thus, chiasma interference seems to provide similar expression in males and females in agreement with the situation in humans, where oocytes with longer SCs display a higher level of recombination that is not a consequence of more closely spaced crossovers along the SCs.

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Mlh1 Deficiency in Zebrafish Results in Male Sterility and Aneuploid as Well as Triploid Progeny in Females

Cited by 74 publications

References 35 publications

Zebrafish with Mutations in Mismatch Repair Genes Develop Neurofibromas and Other Tumors

Zebrafish with Mutations in Mismatch Repair Genes Develop Neurofibromas and Other Tumors

Cyp17a1 and Cyp19a1 in the zebrafish testis are differentially affected by oestradiol

Sex-specific crossover patterns in Zebrafish (Danio rerio)

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