Phenotype of theCyp1a1/1a2/1b1(-/-) Triple-Knockout Mouse

Dragin, Nadine; Shi, Zhanquan; Madan, Rajat; Karp, Christopher L.; Sartor, Maureen A.; Chen, Chi; Gonzalez, Frank J.; Nebert, Daniel W.

doi:10.1124/mol.108.045658

Cited by 62 publications

(56 citation statements)

References 69 publications

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“…Ablation of all three Cyp1 genes results in a phenotype: incomplete penetrance for greater risk of embryolethality before gestational day(GD)-11, hydrocephalus, hermaphroditism and cystic ovaries; intriguingly, however, about one of every 40 F 1 pups survive and eventually breed, leading to loss of the above-mentioned traits [42]. Because this improvement in phenotype happens in only one or two generations, it is likely that epigenetics is involved in such selective breeding [42,43]. Nevertheless, because defects in implantation, growth in utero, hydrocephalus, hermaphroditism and cystic ovaries all are very likely to reflect disturbances in eicosanoid actions (table 3), data from the Cyp1a1/1a2/1b1(2/2) triple-knockout mouse line reinforce the tenet that removal of the entire Cyp1 gene family is able to perturb eicosanoid-mediated functions in dramatic fashion.…”

Section: (D) Roles Of Electron-donating Redox Partners In Cyp Activitiesmentioning

confidence: 99%

Human cytochromes P450 in health and disease

Nebert

Wikvall

Miller

2013

Phil. Trans. R. Soc. B

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425

305

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There are 18 mammalian cytochrome P450 (CYP) families, which encode 57 genes in the human genome. CYP2, CYP3 and CYP4 families contain far more genes than the other 15 families; these three families are also the ones that are dramatically larger in rodent genomes. Most (if not all) genes in the CYP1, CYP2, CYP3 and CYP4 families encode enzymes involved in eicosanoid metabolism and are inducible by various environmental stimuli (i.e. diet, chemical inducers, drugs, pheromones, etc.), whereas the other 14 gene families often have only a single member, and are rarely if ever inducible or redundant. Although the CYP2 and CYP3 families can be regarded as largely redundant and promiscuous, mutations or other defects in one or more genes of the remaining 16 gene families are primarily the ones responsible for P450-specific diseases-confirming these genes are not superfluous or promiscuous but rather are more directly involved in critical life functions. P450-mediated diseases comprise those caused by: aberrant steroidogenesis; defects in fatty acid, cholesterol and bile acid pathways; vitamin D dysregulation and retinoid (as well as putative eicosanoid) dysregulation during fertilization, implantation, embryogenesis, foetogenesis and neonatal development.

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Section: (D) Roles Of Electron-donating Redox Partners In Cyp Activitiesmentioning

confidence: 99%

Human cytochromes P450 in health and disease

Nebert

Wikvall

Miller

2013

Phil. Trans. R. Soc. B

Self Cite

425

305

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“…Phenotype of the Cyp1a1/1a2/1b1 Ϫ/Ϫ Mouse-When compared with wild-type mice (with incomplete penetrance), the Cyp1 triple-knock-out F 1 mouse exhibited (i) infertility and embryo lethality, (ii) a significantly increased risk of certain birth defects (hydrocephalus, hermaphroditism, and cystic ovaries), and (iii) at least 89 genes significantly up-regulated versus 62 genes down-regulated (6). All of these phenotypes probably reflect deficiencies in cell proliferation and migration, ion transport, angiogenesis, and/or vascular pO 2 sensing, again most likely eicosanoid-related processes (supplemental Table S2).…”

Section: Cyp1a1/1a2/1b1mentioning

confidence: 99%

Endogenous Functions of the Aryl Hydrocarbon Receptor (AHR): Intersection of Cytochrome P450 1 (CYP1)-metabolized Eicosanoids and AHR Biology

Nebert

Karp

2008

Journal of Biological Chemistry

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144

121

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“…Cyp1b1-null mice are phenotypically normal probably because of redundancy and compensation by other CYP1 members [48]. Triple knockout (Cyp1a1/Cyp1a2/Cyp1b1) mice exhibit pseudohermaphroditism (retention of Müllerian and Wolffian duct derivatives) and bilateral cystic ovaries [49]. Thus, CYP1 members are important for sexual development and masculinization.…”

Section: /Map2k2mentioning

confidence: 99%

Novel Targets for the Transcription Factors MEF2 in MA-10 Leydig Cells1

Di-Luoffo

Daems

Bergeron

et al. 2015

Biology of Reproduction

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Testosterone production by Leydig cells is a tightly regulated process requiring synchronized expression of several steroidogenic genes by numerous transcription factors. Myocyte enhancer factor 2 (MEF2) are transcription factors recently identified in somatic cells of the male gonad. In other tissues, MEF2 factors are essential regulators of organogenesis and cell differentiation. So far in the testis, MEF2 factors were found to regulate Leydig cell steroidogenesis by controlling Nr4a1 and Star gene expression. To expand our understanding of the role of MEF2 in Leydig cells, we performed microarray analyses of MEF2-depleted MA-10 Leydig cells, and the results were analyzed using Partek and Ingenuity Pathway Analysis software. Several genes were differentially expressed in MEF2-depleted Leydig cells, and 16 were validated by quantitative RT-PCR. A large number of these genes are known to be involved in fertility, gonad morphology, and steroidogenesis. These include Ahr, Bmal1, Cyp1b1, Hsd3b1, Hsd17b7, Map2k1, Nr0b2, Pde8a, Por, Smad4, Star, and Tsc22d3, which were all downregulated in the absence of MEF2. In silico analyses revealed the presence of MEF2-binding sites within the first 2 kb upstream of the transcription start site of the Por, Bmal1, and Nr0b2 promoters, suggesting direct regulation by MEF2. Using transient transfections in MA-10 Leydig cells, small interfering RNA knockdown, and a MEF2-Engrailed dominant negative, we found that MEF2 activates the Por, Bmal1, and Nr0b2 promoters and that this requires an intact MEF2 element. Our results identify novel target genes for MEF2 and define MEF2 as an important regulator of Leydig cell function and male reproduction. fertility, gonad morphology, Leydig cells, microarray, myocyte enhancer factor 2, steroidogenesis

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Phenotype of theCyp1a1/1a2/1b1(-/-) Triple-Knockout Mouse

Cited by 62 publications

References 69 publications

Human cytochromes P450 in health and disease

Human cytochromes P450 in health and disease

Endogenous Functions of the Aryl Hydrocarbon Receptor (AHR): Intersection of Cytochrome P450 1 (CYP1)-metabolized Eicosanoids and AHR Biology

Novel Targets for the Transcription Factors MEF2 in MA-10 Leydig Cells1

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