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Noveroske JK Lai L Gaussin V Northrop JL Nakamura H Hirschi KK Justice MJ 《Genesis (New York, N.Y. : 2000)》2002,32(3):218-230
For nearly 40 years functional studies of the mouse quaking gene (qkI) have focused on its role in the postnatal central nervous system during myelination. However, the homozygous lethality of a number of ENU-induced alleles reveals that quaking has a critical role in embryonic development prior to the start of myelination. In this article, we show that quaking has a previously unsuspected and essential role in blood vessel development. Interestingly, we found that quaking, a nonsecreted protein, is expressed in the yolk sac endoderm, adjacent to the mesodermal site of developing blood islands, where the differentiation of blood and endothelial cells first occurs. Antibodies against PE-CAM-1, TIE-2 and SM-alpha-actin reveal that embryos homozygous for the qk(k2) allele have defective yolk sac vascular remodeling and abnormal vessels in the embryo proper at midgestation, coinciding with the timing of embryonic death. However, these mutants exhibit normal expression of Nkx2.5 and alpha-sarcomeric actin, indicating that cardiac muscle differentiation was normal. Further, they had normal embryonic heart rates in culture, suggesting that cardiac function was not compromised at this stage of embryonic development. Together, these results suggest that quaking plays an essential role in vascular development and that the blood vessel defects are the cause of embryonic death. 相似文献
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The neurological mutant quaking viable is Parkin deficient 总被引:4,自引:0,他引:4
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Janice K. Noveroske Jeffrey A. MacCabe 《In vitro cellular & developmental biology. Animal》1998,34(2):174-181
Summary Two regions of programmed cell death that occur in the mesoderm of developing chick wing buds were studied in vitro. The opaque patch (OP) and posterior necrotic zone (PNZ) were examined for the presence of internucleosomal DNA degradation
and for rescue by protein synthesis inhibition, two defining characteristics of apoptosis. Agarose gel electrophoresis showed
that DNA from OP and PNZ tissue was cleaved into nucleosome size pieces and this cleavage was prevented by inhibition of protein
synthesis with cycloheximide. Both regions showed rescue with cycloheximide as determined by the chromium release assay and
examination of electron micrographs. Also, the permanence of basic fibroblast growth factor (FGF-2) rescue in the OP and PNZ
was examined using the chromium release assay. While rescue in the OP was found to be permanent, rescue in the PNZ only delayed
death while FGF-2 was present in the culture medium. This research shows that death in the OP and PNZ exhibits internucleosomal
DNA fragmentation and is prevented by inhibition of protein synthesis with cycloheximide, biochemically characterizing this
death as apoptosis. It also suggests that in vitro FGF-2 rescue is permanent in the OP but is merely a delay of cell death in the PNZ. 相似文献
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The mutagenic action of N-ethyl-N-nitrosourea in the mouse 总被引:5,自引:0,他引:5
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Roger D. Cox Alison Hugill Alexandra Shedlovsky Janice K. Noveroske Steve Best Monica J. Justice Hans Lehrach William F. Dove 《Genomics》1999,57(3):333
Multiple alleles of the quaking (qk) gene have a variety of phenotypes ranging in severity from early embryonic death to viable dysmyelination. A previous study identified a candidate gene, QKI, that contains an RNA-binding domain and encodes at least three protein isoforms (QKI-5, -6 and -7). We have determined the genomic structure of QKI, identifying an additional alternative end in cDNAs. Further we have examined the exons and splice sites for mutations in the lethal allelesqkl-1, qkkt1, qkk2,andqkkt3.The mutation inqkl-1creates a splice site in the terminal exon of the QKI-6 isoform. Missense mutations in the KH domain and the QUA1 domains inqkk2andqkkt3,respectively, indicate that these domains are of critical functional importance. Although homozygotes for each ENU induced allele die as embryos, their phenotypes as viable compound heterozygotes with qkvdiffer. Compound heterozygousqkvanimals carryingqkkt1, qkk2,andqkkt3all exhibit a permanent quaking phenotype similar to that ofqkv/qkvanimals, whereasqkv/qkl-1animals exhibit only a transient quaking phenotype. Theqkl-1mutation eliminates the QKI-5 isoform, showing that this isoform plays a crucial role in embryonic survival. The transient quaking phenotype observed inqkv/qkl-1mice indicates that the QKI-6 and QKI-7 isoforms function primarily during myelination, but that QKI-5 may have a concentration-dependent role in early myelination. This mutational analysis demonstrates the power of series of alleles to examine the function of complex loci and suggests that additional mutant alleles of quaking could reveal additional functions of this complex gene. 相似文献
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R D Cox A Hugill A Shedlovsky J K Noveroske S Best M J Justice H Lehrach W F Dove 《Genomics》1999,57(3):333-341
Multiple alleles of the quaking (qk) gene have a variety of phenotypes ranging in severity from early embryonic death to viable dysmyelination. A previous study identified a candidate gene, QKI, that contains an RNA-binding domain and encodes at least three protein isoforms (QKI-5, -6 and -7). We have determined the genomic structure of QKI, identifying an additional alternative end in cDNAs. Further we have examined the exons and splice sites for mutations in the lethal alleles qkl-1, qkkt1, qkk2, and qkkt3. The mutation in qkl-1 creates a splice site in the terminal exon of the QKI-6 isoform. Missense mutations in the KH domain and the QUA1 domains in qkk2 and qkkt3, respectively, indicate that these domains are of critical functional importance. Although homozygotes for each ENU induced allele die as embryos, their phenotypes as viable compound heterozygotes with qkv differ. Compound heterozygous qkv animals carrying qkkt1, qkk2, and qkkt3 all exhibit a permanent quaking phenotype similar to that of qkv/qkv animals, whereas qkv/qkl-1 animals exhibit only a transient quaking phenotype. The qkl-1 mutation eliminates the QKI-5 isoform, showing that this isoform plays a crucial role in embryonic survival. The transient quaking phenotype observed in qkv/qkl-1 mice indicates that the QKI-6 and QKI-7 isoforms function primarily during myelination, but that QKI-5 may have a concentration-dependent role in early myelination. This mutational analysis demonstrates the power of series of alleles to examine the function of complex loci and suggests that additional mutant alleles of quaking could reveal additional functions of this complex gene. 相似文献
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Janice K. Noveroske Rebecca Hardy Jason D. Dapper Hannes Vogel Monica J. Justice 《Mammalian genome》2005,16(9):672-682
The mutant allelic series of the mouse quaking gene consists of the spontaneous quakingviable (qkv) allele, which is homozygous viable with a dysmyelination phenotype, and four ENU-induced alleles (qkkt1, qkk2, qkkt3/4, and qkl-1), which are homozygous embryonic lethal. Here we report the isolation of qke5, the first ENU-induced viable allele of quaking. Unlike qkv/qkv, qke5/qke5 animals have early-onset seizures, severe ataxia, and a dramatically reduced lifespan. Ultrastructural analysis of qke5/qke5 brains reveals severe dysmyelination when compared with both wild-type and qkv/qkv brains. In addition, Calbindin detection in young adult qke5/qke5 mice reveals Purkinje cell axonal swellings indicative of neurodegeneration , which is not seen in young adult qkv/qkv mice. Although the molecular defect in the qke5 allele is not evident by sequencing, protein expression studies show that qke5/qke5 postnatal oligodendrocytes lack the QKI-6 and QKI-7 isoforms and have reduced QKI-5 levels. The oligodendrocyte developmental
markers PDGFαR, NG2, O4, CNP, and MBP are also present in the qke5/qke5 postnatal brain although CNP and MBP levels are considerably reduced. Because the qkv allele is a large deletion that affects the expression of three genes, the new neurologic qke5 allele is an important addition to this allelic series. 相似文献
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