Targeted disruption of the CD3 eta locus causes high lethality in mice: modulation of Oct-1 transcription on the opposite strand.

Ohno, Hiroshi; Goto, Shigemasa; Taki, Shinsuke; Shirasawa, Takuji; Nakano, Hiroshi; Miyatake, Shoichiro; Aoe, Tomohiko; Ishida, Yasumasa; Maeda, Hideyasu R.; Shirai, Tetsu

doi:10.1002/j.1460-2075.1994.tb06365.x

Cited by 35 publications

(8 citation statements)

References 48 publications

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“…Concerning differences between the phenotype of the KO mice in this paper and those of the preceding papers, we consider it may be due to a difference in the structure of the targeting vectors because similar discrepancies were reported several times in the past (Ohno et al, 1994;Olson et al, 1996). In these cases, a difference in the position or direction of the promoter and drug resistance gene was reported to affect the expression or splicing of neighboring genes.…”

Section: Discussionmentioning

confidence: 57%

The Role of PKD in Cell Polarity, Biosynthetic Pathways, and Organelle/F-actin Distribution

Atik

Kunii

Avriyanti

et al. 2014

Cell Struct. Funct.

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ABSTRACT. Protein Kinase D (PKD) 1, 2, and 3 are members of the PKD family. PKDs influence many cellular processes, including cell polarity, structure of the Golgi, polarized transport from the Golgi to the basolateral plasma membrane, and actin polymerization. However, the role of the PKD family in cell polarity has not yet been elucidated in vivo. Here, we show that KO mice displayed similar localization of the apical and basolateral proteins, transport of VSV-G and a GPI-anchored protein, and similar localization of actin filaments. As DKO mice were embryonic lethal, we generated MEFs that lacked all PKD isoforms from the PKD1 and PKD2 double floxed mice using Cre recombinase and PKD3 siRNA. We observed a similar localization of various organelles, a similar time course in the transport of VSV-G and a GPI-anchored protein, and a similar distribution of F-actin in the PKD-null MEFs. Collectively, our results demonstrate that the complete deletion of PKDs does not affect the transport of VSV-G or a GPI-anchored protein, and the distribution of F-actin. However, simultaneous deletion of PKD1 and PKD2 affect embryonic development, demonstrating their functional redundancy during development.

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Section: Discussionmentioning

confidence: 57%

The Role of PKD in Cell Polarity, Biosynthetic Pathways, and Organelle/F-actin Distribution

Atik

Kunii

Avriyanti

et al. 2014

Cell Struct. Funct.

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“…Because it is difficult to reconcile the function of a nuclear DNA polymerase with a defect in axonemal structure (missing IDA), we examined the deletion construct in more detail and determined that another gene was also likely disrupted in the mouse model. Other reports have also documented the disruption of more than one gene in mouse models (22,23). Therefore, the results from any genetically modified animal should be interpreted with caution, especially if the phenotype observed does not agree with the known function of the targeted gene.…”

Section: Discussionmentioning

confidence: 91%

Investigation of the Possible Role of a Novel Gene, DPCD, in Primary Ciliary Dyskinesia

Zariwala

O’Neal

Noone

et al. 2004

Am J Respir Cell Mol Biol

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Primary ciliary dyskinesia (PCD) is an autosomal recessive disease caused by mutations that affect the proper function of cilia. Recently, deletion of DNA polymerase lambda (Poll) in mice produced a phenotype characteristic of PCD (Kobayashi et al., 2002, Mol. Cell. Biol. 22:2769-2776). Because it is unclear how a mutation in a DNA polymerase would result in a specific defect in axonemes, the targeting construct was examined further. Analysis of the genomic region surrounding the Poll gene revealed an uncharacterized gene, named Dpcd, that is predicted to be transcribed from the opposite strand relative to Poll. The deletion of Poll would also remove the first exon of Dpcd. Because it is possible that the PCD phenotype observed is due to the absence of either gene, the expression of these genes during ciliogenesis of human airway epithelial cells was examined. Northern analysis demonstrated that DPCD expression increases during ciliated cell differentiation; the expression of POLL decreases. To examine directly whether DPCD is mutated in cases of human PCD, the complete coding sequence of DPCD was sequenced from 51 unrelated PCD patients. No disease-causing mutations were confirmed; however, one variant could not be excluded. Therefore, DPCD remains a novel candidate gene for PCD.

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“…Sequencing the exon-intron boundaries of mouse exons 3 to 7 and comparison to known human sequences (59) showed that the genomic organization was conserved. Previous studies have shown that targeted disruption of exon 9 in the CD3 locus also affected Oct-1 transcription due to overlap of the 3Ј regions of the two genes (28,31,41). To avoid disrupting the CD3 locus, a strategy was designed to inactivate Oct-1 by targeting the 5Ј end.…”

Section: Resultsmentioning

confidence: 99%

Embryonic Lethality, Decreased Erythropoiesis, and Defective Octamer-Dependent Promoter Activation in Oct-1-Deficient Mice

Wang

Schmidt

Chen

et al. 2004

Molecular and Cellular Biology

111

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Oct-1 is a sequence-specific DNA binding transcription factor that is believed to regulate a large group of tissue-specific and ubiquitous genes. Both Oct-1 and the related but tissue-restricted Oct-2 protein bind to a DNA sequence termed the octamer motif (5-ATGCAAAT-3) with equal affinity in vitro. To address the role of Oct-1 in vivo, an Oct-1-deficient mouse strain was generated by gene targeting. Oct-1-deficient embryos died during gestation, frequently appeared anemic, and suffered from a lack of Ter-119-positive erythroid precursor cells. This defect was cell intrinsic. Fibroblasts derived from these embryos displayed a dramatic decrease in Oct-1 DNA binding activity and a lack of octamer-dependent promoter activity in transient transfection assays. Interestingly, several endogenous genes thought to be regulated by Oct-1 showed no change in expression. When crossed to Oct-2 ؉/؊ animals, transheterozygotes were recovered at a very low frequency. These findings suggest a critical role for Oct-1 during development and a stringent gene dosage effect with Oct-2 in mediating postnatal survival.Gene expression is mediated by the interaction of transacting factors with cis-acting elements in promoters and enhancers. The octamer-binding proteins Oct-1 and Oct-2 control gene expression by interacting with the octamer element 5Ј-ATGCAAAT-3Ј and related motifs (6,50,54,55,57). Their DNA binding domains are highly homologous, and both proteins bind DNA with equal affinity in vitro (29). Expression studies indicate that Oct-1 is ubiquitously expressed, whereas Oct-2 is restricted to B cells, macrophages, and other hematopoietic cells, as well as cells of the central nervous system.Oct-1 and Oct-2 belong to the POU domain family of transcription factors, which was identified after the isolation of three mammalian transcription factors and a Caenorhabditis elegans developmental regulator: Pit-1, Oct-1, Oct-2 and unc-86 (16). The POU domain consists of a bipartite DNAbinding motif, the POU-specific and POU homeodomain, tethered by a linker domain of approximately 20 amino acids (60, 66). X-ray crystallography studies reveal that the POU subdomains of Oct-1 both contact the major groove but on opposite sides of the DNA (26), with the POU-specific domain contacting the 5Ј-ATGC subsite and the POU homeodomain binding the AAAT-3Ј subsite. Such cooperative binding between adjacent subdomains resulting in the recognition of asymmetrical DNA motifs is characteristic of POU domain transcription factors.With the exception of the ubiquitously expressed Oct-1, all of the known mouse POU domain factors are expressed in restricted temporal and spatial patterns during development (reviewed in reference 49). Gene targeting experiments have provided direct evidence that the POU domain proteins play a critical role in the determination of cell fates. For example, deficiency of the POU domain protein Pit-1 results in pituitary hypoplasia and dwarfism (33,44). Mutation of Brn-3

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Targeted disruption of the CD3 eta locus causes high lethality in mice: modulation of Oct-1 transcription on the opposite strand.

Cited by 35 publications

References 48 publications

The Role of PKD in Cell Polarity, Biosynthetic Pathways, and Organelle/F-actin Distribution

The Role of PKD in Cell Polarity, Biosynthetic Pathways, and Organelle/F-actin Distribution

Investigation of the Possible Role of a Novel Gene, DPCD, in Primary Ciliary Dyskinesia

Embryonic Lethality, Decreased Erythropoiesis, and Defective Octamer-Dependent Promoter Activation in Oct-1-Deficient Mice

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