Animal model of Gaucher's disease from targeted disruption of the mouse glucocerebrosidase gene

Tybulewicz, Victor L. J.; Tremblay, Michel L.; LaMarca,; Willemsen, Rob; Stubblefield, Barbara; Winfield, Suzanne; Zabłocka, Barbara; Sidransky, Ellen; Martin, Brian M.; Huang, Sing-Ping; Mintzer, K. A.; Westphal, Heiner; Mulligan, Richard C.; Ginns, Edward I.

doi:10.1038/357407a0

Cited by 279 publications

(180 citation statements)

References 16 publications

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“…The 12.5-kb genomic fragment contained ϳ4 kb of 5Ј-flanking DNA and extended to the middle of exon 8. The targeting vector was constructed by cloning a 1.8-kb phosphoglycerate kinase (PGK) Neo cassette (43) into the EcoRI/HindIII site of pBluescript SK (Stratagene). The 3Ј end of the targeting construct consisted of a 2-kb mouse P450c17 fragment, generated by digesting the P450c17 genomic clone with AvaI/SstI and blunting the ends with deoxynucleoside triphosphates and DNA polymerase.…”

Section: Methodsmentioning

confidence: 99%

Deletion of the Mouse P450c17 Gene Causes Early Embryonic Lethality

Bair

Mellon

2004

Molecular and Cellular Biology

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Dehydroepiandrosterone (DHEA), a 19-carbon precursor of sex steroids, is abundantly produced in the human but not the mouse adrenal. However, mice produce DHEA and DHEA-sulfate (DHEAS) in the fetal brain. DHEA stimulates axonal growth from specific populations of mouse neocortical neurons in vitro, while DHEAS stimulates dendritic growth from those cells. The synthesis of DHEA and sex steroids, but not mouse glucocorticoids and mineralocorticoids, requires P450c17, which catalyzes both 17␣-hydroxylase and 17,20-lyase activities. We hypothesized that P450c17-knockout mice would have disordered sex steroid synthesis and disordered brain DHEA production and thus provide phenotypic clues about the functions of DHEA in mouse brain development. We deleted the mouse P450c17 gene in 127/SvJ mice and obtained several lines of mice from two lines of targeted embryonic stem cells. Heterozygotes were phenotypically and reproductively normal, but in all mouse lines, P450c17 ؊/؊ zygotes died by embryonic day 7, prior to gastrulation. The cause of this early lethality is unknown, as there is no known function of fetal steroids at embryonic day 7. Immunocytochemistry identified P450c17 in embryonic endoderm in E7 wild-type and heterozygous embryos, but its function in these cells is unknown. Enzyme assays of wild-type embryos showed a rapid rise in 17-hydroxylase activity between E6 and E7 and the presence of C 17,20 -lyase activity at E7. Treatment of pregnant females with subcutaneous pellets releasing DHEA or 17-OH pregnenolone at a constant rate failed to rescue P450c17 ؊/؊ fetuses. Treatment of normal pregnant females with pellets releasing pregnenolone or progesterone did not cause fetal demise. These data suggest that steroid products of P450c17 have heretofore-unknown essential functions in early embryonic mouse development.

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Section: Methodsmentioning

confidence: 99%

Deletion of the Mouse P450c17 Gene Causes Early Embryonic Lethality

Bair

Mellon

2004

Molecular and Cellular Biology

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“…Genetic defects in several of these hydrolytic enzymes cause various disorders with lysosomal accumulation of the substrate lipids, a group of disorders termed the sphingolipidoses [41,[90][91][92][93]. Particularly, some of the known sphingolipidoses might closely associate with aberrant metabolisms of ceramide because of defective activities of ceramide generating/degrading enzymes: Farber's disease, Gaucher disease, and Niemann-Pick type A and B diseases are caused by a deficiency of acid ceramidase [94,95], glucocerebrosidase (acid-β-glucosidase) [96][97][98], acid SMase [99,100], respectively. The salvage pathway is one of the routes for controlling cellular levels of ceramide.…”

Section: Sphingolipidosesmentioning

confidence: 99%

The sphingolipid salvage pathway in ceramide metabolism and signaling

Kitatani

Idkowiak‐Baldys

Hannun

2008

Cellular Signalling

539

457

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Sphingolipids are important components of eukaryotic cells, many of which function as bioactive signaling molecules. Of these, ceramide is a central metabolite and plays key roles in a variety of cellular responses, including regulation of cell growth, viability, differentiation, and senescence. Ceramide is composed of the long-chain sphingoid base, sphingosine, in N-linkage to a variety of acyl groups. Sphingosine serves as the product of sphingolipid catabolism, and it is mostly salvaged through re-acylation, resulting in the generation of ceramide or its derivatives. This recycling of sphingosine is termed the "salvage pathway", and recent evidence points to important roles for this pathway in ceramide metabolism and function. A number of enzymes are involved in the salvage pathway, and these include sphingomyelinases, cerebrosidases, ceramidases, and ceramide synthases. Recent studies suggest that the salvage pathway is not only subject to regulation, but it also modulates the formation of ceramide and subsequent ceramide-dependent cellular signals. This review focuses on the salvage pathway in ceramide metabolism, its regulation, its experimental analysis, and emerging biological functions.

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“…10--15 ES cells from two independent clones, EPl-26 and EP2-173, were microinjected into each blastocoel cavity (26). The blastocysts were then reimplanted into the uterine horn of pseudopregnant CD1 mice.…”

Section: Blastocyst Injection and Animal Breeding Blastocysts Were Omentioning

confidence: 99%

The Ity/Lsh/Bcg locus: natural resistance to infection with intracellular parasites is abrogated by disruption of the Nramp1 gene.

Vidal

Tremblay

Govoni

et al. 1995

The Journal of Experimental Medicine

555

337

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SummaryIn mice, natural resistance or susceptibility to infection with intracellular parasites is determined by a locus or group of loci on chromosome 1, designated Bcg, Lsh, and Ity, which controls early microbial replication in reticuloendothelial organs. We have identified by positional cloning a candidate gene for Beg, Nrampl, which codes for a novel macrophage-specific membrane transport protein. We have created a mouse mutant bearing a null allele at Nrampl, and we have analyzed the effect of such a mutation on natural resistance to infection. Targeted disruption of Nrampl has pleiotropic effects on natural resistance to infection with intracellular parasites, as it eliminated resistance to Mycobacterium boris, Leishmania donovani, and lethal Salmonella typhimurium infection, establishing that Nrampl, Bcg, Lsh, and It), are the same locus. Comparing the profiles of parasite replication in control and Nrampl -/-mice indicated that the NramplAse 169 allele of Beg s inbred strains is a null allele, pointing to a critical role of this residue in the mechanism of action of the protein. Despite their inability to control parasite growth in the early nonimmune phase of the infection, Nrampl -/-mutants can overcome the infection in the late immune phase, suggesting that Nrampl plays a key role only in the early part of the macrophage-parasite interaction and may function by a cytocidal or cytostatic mechanism distinct from those expressed by activated macrophages.

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Animal model of Gaucher's disease from targeted disruption of the mouse glucocerebrosidase gene

Cited by 279 publications

References 16 publications

Deletion of the Mouse P450c17 Gene Causes Early Embryonic Lethality

Deletion of the Mouse P450c17 Gene Causes Early Embryonic Lethality

The sphingolipid salvage pathway in ceramide metabolism and signaling

The Ity/Lsh/Bcg locus: natural resistance to infection with intracellular parasites is abrogated by disruption of the Nramp1 gene.

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