Characterization of Ayu17-449 gene expression and resultant kidney pathology in a knockout mouse model

Tang, Hua; Araki, Kimi; Li, Zhenghua; Yamamura, Ken‐ichi

doi:10.1007/s11248-008-9170-y

Cited by 12 publications

(18 citation statements)

References 31 publications

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“…21 However, we observed no abnormalities in kidneys from TET2 trap/trap mice (Supplementary Figure S1). Acidic granules in the proximal convoluted tubules of the kidneys in TET2 trap/trap mice were observed as is the case in those in WT mice.…”

Section: In Bm Compartments Including Linmentioning

confidence: 77%

“…21 We obtained the mice from the mutant mouse resource of Trans Genic Inc. (Kobe, Japan). A gene trap vector containing a splice acceptor followed by the b-galactosidase/neomycin resistance fusion cassette disrupts the TET2 gene locus by inserting into intron 2 ( Figure 1a).…”

Section: Materials and Methods Micementioning

confidence: 99%

“…21 in which a gene trap vector was inserted into intron 2 of TET2 (Figure 1a). The expected single 4.8-kb band was detected on a Southern blot of tail DNA digested with EcoRI and hybridized with probe A (Figure 1b (Table 1).…”

Section: Pathological Examinationmentioning

confidence: 99%

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TET2 is essential for survival and hematopoietic stem cell homeostasis

et al. 2012

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Ten-Eleven-Translocation 2 (TET2) is an enzyme that catalyzes the conversion of 5-methylcytosine into 5-hydroxymethylcytosine (5-hmC) and thereby alters the epigenetic state of DNA; somatic loss-of-function mutations of TET2 are frequently observed in patients with diverse myeloid malignancies. To study the function of TET2 in vivo, we analyzed Ayu17-449 (TET2 trap ) mice, in which a gene trap insertion in intron 2 of TET2 reduces TET2 mRNA levels to about 20% of that found in wild-type (WT) mice. TET2 trap/trap mice were born at Mendelian frequency but died at a high rate by postnatal day 3, indicating the essential role of TET2 for survival. Loss of TET2 results in an increase in the number of hematopoietic stem cells (HSCs)/progenitors in the fetal liver, and TET2 trap/trapHSCs exhibit an increased self-renewal ability in vivo. In competitive transplantation assays, TET2 trap/trap HSCs possess a competitive growth advantage over WT HSCs. These data indicate that TET2 has a critical role in survival and HSC homeostasis. (2012) 26, 2216-2223; doi:10.1038/leu.2012.94 Keywords: TET2; myeloproliferative neoplasms; tumor suppressor; animal models; hematopoietic stem cells Leukemia INTRODUCTIONMyeloproliferative neoplasms (MPNs) are characterized by an overproduction of white blood cells and are frequently associated with a somatic Janus kinase 2 (JAK2) V617F mutation that results in a constitutively active protein. [1][2][3][4] The presence of JAK2 V617F alone can cause MPN in mouse models, 5-9 but does not confer a growth advantage upon hematopoietic stem cells (HSCs). 9In female MPN patients tested for JAK2 mutations and X-chromosomal clonality, the percentage of granulocytes and platelets with a JAK2 mutation was often markedly lower than the percentage of clonal granulocytes. 10,11 In addition, JAK2-V617F-positive MPNs are frequently found in patients with JAK2-V617F-negative acute myeloid leukemia. 12 These data suggest that the MPN cells expand clonally before acquisition of a JAK2 mutation, and that the leukemic transformation shares a common clonal origin in MPN and acute myeloid leukemia.Mutations in Ten-Eleven-Translocation-2 (TET2) have also been observed in 10-20% of patients with MPN,13,14 as well as in patients with myelodysplastic syndrome, chronic myelomonocytic leukemia and acute myeloid leukemia, [14][15][16][17] suggesting that mutation of TET2 is a common pathogenetic event in myeloid malignancies. TET family members share a highly conserved catalytic domain, and both TET1 and TET2 catalyze the conversion of 5-methylcytosine into 5-hmC, [18][19][20] resulting in the modification of DNA. The amount of 5-hmC in DNA from patients with myeloid malignancies was lower when they possessed a TET2 mutation than when they did not, 19 suggesting that the mutant TET2 protein was defective in its enzymatic function. Recent work has shown that small hairpin RNA-mediated depletion of TET2 in murine hematopoietic precursors alters their differentiation toward monocyte/macrophage lineages in vitro, suggesting...

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Section: In Bm Compartments Including Linmentioning

confidence: 77%

Section: Materials and Methods Micementioning

confidence: 99%

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TET2 is essential for survival and hematopoietic stem cell homeostasis

et al. 2012

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“…Tang et al (2008) showed that in Ayu17-449 null mice, development appears largely normal until embryonic day 19 (E19), and embryos die (at P0-P1) from unidentified causes. In adult mice, Ayu17-449 showed a characteristic regional distribution in brain and kidney.…”

Section: Introductionmentioning

confidence: 99%

“…In adult mice, Ayu17-449 showed a characteristic regional distribution in brain and kidney. Ayu17-449 was identified having the granin motif, which was important for acidic granule formation in mouse proximal convoluted tubules (Tang et al, 2008). However, detailed information on the functions of granules in the proximal tubule cell was as yet unavailable.…”

Section: Introductionmentioning

confidence: 99%

Gene expression profiling: identification of genes with altered expression in Ayu17-449 knockout mice

Huang

Tang

et al. 2011

Genet. Mol. Res.

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ABSTRACT. Ayu17-449, a novel gene in mice, has been identified as a tumor-suppressor gene in myeloid malignancy; its product catalyzes the conversion of 5-methylcytosine of DNA to 5-hydroxymethylcytosine. However, in vivo, its functional target genes and biological function have remained unclear. Based on the assumption that alterations in the expression of the Ayu17-449 gene affect the expression of other related genes, we screened a microarray of altered gene expression in Ayu17-449 -/-and Ayu17-449 +/+ mice. We identified 4049 genes with altered expression, including 1296 upregulated (fold change ≥2) and 2753 down-regulated (fold change ≤0.5) genes in knockout mice compared with control mice. We then used qRT-PCR and RT-PCR to validate the chip data. Gene ontology and pathway analysis were performed on these altered genes. We found that these altered genes are functional genes in the complement and coagulation cascades, metabolism, biosynthesis, transcriptional regulation, proteolysis, and intracellular signaling pathways, such as the peroxisome proliferator-activated-receptor signaling pathway, the TNF-α-NF-κB pathway, the Notch signaling pathway, the MAPK signaling pathway, and the insulin signaling pathway. The results of our genome-wide comprehensive study could be helpful for comprehending the underlying functional mechanisms of the Ayu17-449 gene in mammals.

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Genetic polymorphisms among C57BL/6 mouse inbred strains

et al. 2010

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Mice from the inbred C57BL/6 strain have been commonly used for the generation and analysis of transgenic and knockout animal models. However, several C57BL/6 substrains exist, and these are genetically and phenotypically different. In addition, each of these substrains can be purchased from different animal providers and, in some cases, they have maintained their breeding stocks separated for a long time, allowing genetic differences to accumulate due to individual variability and genetic drift. With the aim of describing the differences in the genotype of several C57BL/6 substrains, we applied the Illumina(®) Mouse Medium Density Linkage Mapping panel, with 1,449 single nucleotide polymorphisms (SNPs), to individuals from ten C57BL/6-related strains: C57BL/6JArc, C57BL/6J from The Jackson Lab, C57BL/6J from Crl, C57BL6/JRccHsd, C57BL/6JOlaHsd, C57BL/6JBomTac, B6(Cg)-Tyr ( c-2j )/J, C57BL/6NCrl, C57BL/6NHsd and C57BL/6NTac. Twelve SNPs were found informative to discriminate among the mouse strains considered. Mice derived from the original C57BL/6J: C57BL/6JArc, C57BL/6J from The Jackson Lab and C57BL/6J from Crl, were indistinguishable. Similarly, all C57BL/6N substrains displayed the same genotype, whereas the additional substrains showed intermediate cases with substrain-specific polymorphisms. These results will be instrumental for the correct genetic monitoring and appropriate mouse colony handling of different transgenic and knockout mice produced in distinct C57BL/6 inbred substrains.

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Characterization of Ayu17-449 gene expression and resultant kidney pathology in a knockout mouse model

Cited by 12 publications

References 31 publications

TET2 is essential for survival and hematopoietic stem cell homeostasis

TET2 is essential for survival and hematopoietic stem cell homeostasis

Gene expression profiling: identification of genes with altered expression in Ayu17-449 knockout mice

Genetic polymorphisms among C57BL/6 mouse inbred strains

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