Cloning and Sequencing of the MouseGli2Gene: Localization to theDominant hemimeliaCritical Region

Hughes, David C.; Allen, Jeremy; Morley, Garry; Sutherland, Kate D.; Ahmed, Wasim; Prosser, J.; Lettice, Laura A.; Allan, Gordon J.; Matteï, Marie‐Geneviève; Farrall, Martin; Hill, Robert E.

doi:10.1006/geno.1996.4468

Cited by 32 publications

(22 citation statements)

References 5 publications

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“…46 Interestingly, another locus, Ncl, also located at 48.4 cM on Chr 1, 47,48 showed no linkage to the B220% phenotype in the same BXD RI strains (data not shown) because 8 of the 26 BXD RI strains showed crossover between the D1Ncvs44 locus and the Ncl locus. Whether or not the D1Ncvs44 locus is polymorphic between B6 and SJL mice is yet to be defined.…”

Section: Qtl Mappingmentioning

confidence: 99%

Quantitative trait loci regulating relative lymphocyte proportions in mouse peripheral blood

Chen

Harrison

2002

Blood

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Relative proportions of peripheral blood (PB) B lymphocytes (B220%) as well as CD4 (CD4%) and CD8 (CD8%) T lymphocytes differ significantly among inbred mouse strains: B220% is high in C57BL/6J (B6) and C57BR/cdJ, intermediate in BALB/cByJ (BALB) and DBA/2J (D2), and low in NOD/LtJ (NOD) and SJL/J (SJL) mice, whereas CD4% and CD8% are high in NOD and SJL mice and low in the other 4 strains. By following segregating genetic markers linked to these traits in (B6 ؋ D2) recombinant inbred (BXD RI) mice, the study defined 2 quantitative trait loci (QTLs) for the B220% phenotype: Pbbcp1 (peripheral blood B cell percentage 1, logarithm of odds [LOD] 4.1, P < .000 01) and Pbbcp2 (LOD 3.7, P < .000 04) on chromosome 1 (Chr 1) at about 63 cM and 48 cM; one suggestive locus for the CD4% phenotype (LOD 2.6, P < .000 57) on Chr 8 at about 73 cM; and one QTL for the CD8% phenotype: Pbctlp1 (peripheral blood cytotoxic T lymphocyte percentage 1, LOD 3.8, P < .000 02) on Chr 19 at about 12 cM. The study further segregated PB lymphocyte proportions in B6SJLF2 mice by using DNA markers adjacent to these mapped QTLs and found that the Pbbcp1 locus (LOD 5.6, P < .000 01) was also important in this mouse population. In both BXD RI and B6SJLF2 mice, QTLs regulating B-cell proportions showed no significant effect on T-cell proportions and vice versa. IntroductionMature leukocytes in mouse and human peripheral blood (PB) express specific cell surface molecules (markers) that can be detected by fluorescence-activated cell staining (FACS) using specific antibodies. 1,2 The major categories of PB leukocytes include B lymphocytes that express B220, T-helper lymphocytes that express CD4, cytotoxic T lymphocytes that express CD8, and granulocytes that express Gr1. Under physiologic conditions, proportions of PB leukocyte subsets are relatively constant in mice from a particular genotype, showing a precise regulation of hematopoietic lineage commitment, differentiation, maturation, recruitment, and elimination. 3 Proportions of PB leukocyte subsets can be dramatically altered by spontaneous and induced mutations; for example, a mutation in the DNA-dependent protein kinase gene in severe combined immunedeficient mice results in the absence of mature B and T lymphocytes in blood circulation. [4][5][6] In addition, stromal cells, cytokines, receptors, ligands, signaling molecules, and transcription factors have been shown to affect levels of B and T lymphocytes. [7][8][9][10] Previous studies identified molecular factors that play important roles in the regulation of B-and T-cell commitment and balance such as cytokines interleukin-3 (IL-3) and IL-7, signaling receptor and ligand Notch and Jagged, paired-box gene Pax5, and the transcriptional factors E2A and EBF. 3,[11][12][13] Mutations that change the relative levels of other leukocyte subsets may also indirectly affect B-and T-cell proportions. 14 Earlier studies found that the CD4/CD8 ratio is under genetic control in the mouse as well as in humans. [15][16][17] A study using inbred mouse ...

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Section: Qtl Mappingmentioning

confidence: 99%

Quantitative trait loci regulating relative lymphocyte proportions in mouse peripheral blood

Chen

Harrison

2002

Blood

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“…Additionally, Drosophila CBP recognizes and acetylates a specific sequence in the GLI homologue Ci, thereby activating it [15] . The amino acid sequence recognized by CBP/p300 in Ci is conserved and is also found in GLI2, suggesting that modification by this complex may also activate GLI2 [6,16] . Thus, further description of the role of p300 in regulating GLI2 activity may be identified in future studies.…”

mentioning

confidence: 99%

From Normal Development to Disease: The Biochemistry and Regulation of GLI2

McCleary‐Wheeler¹

2014

Med Epigenet

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GLI2 is an oncogene encoding a unique transcription factor with both repressor and activator functions. Vitally important in development, it is also thought to be necessary for homeostasis of adult cells. However, deregulation of the GLI2 protein can result in detrimental effects to an organism, such as congenital defects or cancer. Historically deemed an activator and effector molecule of the Hedgehog signaling pathway, GLI2 has since been shown to be a critical effector of other signaling pathways, thus positioning itself as a potent mediator of signaling crosstalk. While GLI2 activity can be modulated by a variety of signaling influences, its regulation at the gene level is less understood. Indeed, gene mutations in GLI2 have been reported, but these generally led to developmental defects and are less commonly identified in tumors as being a cause of its deregulation. While the biological importance of GLI2 overexpression in a multitude of unrelated cancers has been well established, questions about the mechanisms leading to aberrant expression have remained largely unanswered. Furthering our understanding of both the transcriptional regulation of the GLI2 gene and the target genes regulated by GLI2 may identify novel therapeutic targets for cancer treatment.

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“…Dh exhibits partial or complete loss of the tibia and preaxial digits, a pattern remarkably similar to the proband (Lettice et al 1999). Dh was genetically indistinguishable from Gli2 in 561 meioses, although no Gli2 mutation was identiWed in Dh mice (Hughes et al 1997).…”

Section: Resultsmentioning

confidence: 99%

“…We therefore characterised the breakpoints of the translocation and found that the 2q14.2 breakpoint lies between two genes, INHBB and GLI2 that have both been implicated in limb development. Moreover the breakpoint coincides with the homologous region of the mouse to which the Dominant hemimelia (Dh) limb malformation mutant has been mapped (Hughes et al 1997). We therefore screened the four genes (GLI2, INHBB, RALB and FLJ14816) in proximity to the 2q breakpoint for mutations in 44 patients with limb malformations including SHFM, SHFLD or isolated long bone deWciency; however, no clearly pathogenic mutation was found.…”

Section: Introductionmentioning

confidence: 99%

A new locus for split hand/foot malformation with long bone deficiency (SHFLD) at 2q14.2 identified from a chromosome translocation

et al. 2007

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Split hand/foot malformation (SHFM) with long bone deWciency (SHFLD) is a distinct entity in the spectrum of ectrodactylous limb malformations characterised by associated tibial a/hypoplasia. Pedigrees with multiple individuals aVected by SHFLD often include nonpenetrant intermediate relatives, making genetic mapping diYcult. Here we report a sporadic patient with SHFLD who carries a de novo chromosomal translocation t(2;18)(q14.2;p11.2). Characterisation of the breakpoints revealed that neither disrupts any known gene; however, the chromosome 2 breakpoint lies between GLI2 and INHBB, two genes known to be involved in limb development. To investigate whether mutation of a gene in proximity to the chromosome 2 breakpoint underlies the SHFLD, we sought independent evidence of mutations in GLI2, INHBB and two other genes (RALB and FLJ14816) in 44 unrelated patients with SHFM, SHFLD or isolated long bone deWciency. No convincing pathogenic mutations were found, raising the possibility that a long-range cis acting regulatory element may be disrupted by this translocation. The previous description of a translocation with a 2q14.2 breakpoint associated with ectrodactyly, and the mapping of the ectrodactylous Dominant hemimelia mouse mutation to a region of homologous synteny, suggests that 2q14.2 represents a novel locus for SHFLD.

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Cloning and Sequencing of the MouseGli2Gene: Localization to theDominant hemimeliaCritical Region

Cited by 32 publications

References 5 publications

Quantitative trait loci regulating relative lymphocyte proportions in mouse peripheral blood

Quantitative trait loci regulating relative lymphocyte proportions in mouse peripheral blood

From Normal Development to Disease: The Biochemistry and Regulation of GLI2

A new locus for split hand/foot malformation with long bone deficiency (SHFLD) at 2q14.2 identified from a chromosome translocation

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