The inhibitory glycine receptor is a ligand-gated ion channel protein that occurs in different de... more The inhibitory glycine receptor is a ligand-gated ion channel protein that occurs in different developmentally regulated isoforms in the mammalian central nervous system. Here, we have analyzed genomic clones covering the coding regions of the murine glycine receptor alpha 1 and alpha 2 subunit genes. Both genes contain eight intronic regions with precisely conserved boundaries. The same structure was also found for seven exons of a third homologous gene, alpha 4, identified during screening. The predicted alpha 4 polypeptide displays very high homology to the alpha 2 subunit. Like the alpha 2 gene, the alpha 4 gene maps to the mouse X chromosome. Our data indicate that the genomic organization of glycine receptor alpha subunit genes is conserved during evolution.
X-Chromosome inactivation is characterized by the transcriptional silencing of one of the two X c... more X-Chromosome inactivation is characterized by the transcriptional silencing of one of the two X chromosomes present in somatic cells of the female. Transcriptional silencing of the X chromosome carried by male germ cells having actively entered meiosis is also observed, but it remains to be proved whether the mechanism underlying X-inactivation in the two cases is identical (Lyon 1983). The process of X-inactivation has been somewhat arbitarily divided into three phases: initiation, spreading, and maintenance. Most theories of initiation suggest it is triggered by a developmental cue at strictly programmed specific stages of embryogenesis in the female and spermatogenesis in the male. In the female mouse, X-inactivation first occurs in the trophoectoderm and extraembryonic endoderm at 3.5–4.5 days of gestation. This is followed by the X-inactivation of the tissues of the embryo itself, which occurs at the egg cylinder stage, between days 5.5 and 6.0 of gestation, around the time of uterine implantation (for review, see Epstein 1983; Lyon 1983). The developmental cue that triggers inactivation is thought to be associated with the presence of a “blocking signal” that is produced in limited quantity and binds to a single X chromosome per diploid cell, protecting it from inactivation. Implicit in this model is the idea that prior to, or during, the initial phases of inactivation some sort of counting mechanism is capable of sensing the number of X chromosomes in relation to the autosomal chromosome complement. There is no evidence that this “sensing” is necessarily direct, and it has...
H-2 substitutions on the B6 and AKR backgrounds have been found to decrease allograft resistance ... more H-2 substitutions on the B6 and AKR backgrounds have been found to decrease allograft resistance to the embryonal carcinoma cell line F9. (C57BL/6 x B6.AK-H-2k)F1 and (C57BL/6 x AKR.B6-H-2b)F1 animals show resistance intermediate to that of the respective parental strains and this result, along with that from F2 analyses, suggests that the resistance differential in each congenic pair is under the control of a single semidominant locus. In the C57BL/6 congenic pair, the locus has been shown to lie outside of the H-2, Qua2/3, PGK-2 region of the 17th chromosome.
By using linkage disequilibrium (LD) analysis in 21 strains of known susceptibility to lung cance... more By using linkage disequilibrium (LD) analysis in 21 strains of known susceptibility to lung cancer and by assembling a YAC contig, we mapped to a ∼1.5-Mb region on distal mouse chromosome 6 the Pas1locus, the major determinant of lung cancer predisposition in mice. Our results, on the basis of haplotype and phenetic analysis, suggest that the Pas1s susceptibility allele is shared by several mouse-inbred strains of independent origin, which show either high or intermediate predisposition to lung tumorigenesis. Therefore, the Pas1s allele is probably derived from an ancestral mouse rather than from independent mutations of the same gene. We showed the feasibility of LD in common inbred strains for the fine mapping of disease loci, and provided the biological basis and the reagents for the cloning of the Pas1 gene.
Type 1 diabetes (T1D) is a major disease affecting primarily young children with an incidence in ... more Type 1 diabetes (T1D) is a major disease affecting primarily young children with an incidence in Western societies of around 0.3% by 20 years of age. Although both genetic and environmental factors contribute to the disease aetiology, the precise nature of both the genetic and environmental contribution to human disease onset and progression remains poorly defined. Despite showing some differences from human T1D, rodent models for T1D (Leiter and von Herrath, 2004; von Herrath and Nepom, 2009) and, in particular the nonobese diabetic (NOD) mouse (Atkinson and Leiter, 1999; Kikutani and Makino, 1992), have provided important insights into the disease process, even if they have not yet allowed definitive identification of many of the genetic factors involved in the process. The recent isolation of germline-competent embryonic stem (ES) cells from the NOD mouse strain, and from the rat, will greatly facilitate the functional analysis of T1D in the mouse, and open up the possibility of ...
The inhibitory glycine receptor is a ligand-gated ion channel protein that occurs in different de... more The inhibitory glycine receptor is a ligand-gated ion channel protein that occurs in different developmentally regulated isoforms in the mammalian central nervous system. Here, we have analyzed genomic clones covering the coding regions of the murine glycine receptor alpha 1 and alpha 2 subunit genes. Both genes contain eight intronic regions with precisely conserved boundaries. The same structure was also found for seven exons of a third homologous gene, alpha 4, identified during screening. The predicted alpha 4 polypeptide displays very high homology to the alpha 2 subunit. Like the alpha 2 gene, the alpha 4 gene maps to the mouse X chromosome. Our data indicate that the genomic organization of glycine receptor alpha subunit genes is conserved during evolution.
X-Chromosome inactivation is characterized by the transcriptional silencing of one of the two X c... more X-Chromosome inactivation is characterized by the transcriptional silencing of one of the two X chromosomes present in somatic cells of the female. Transcriptional silencing of the X chromosome carried by male germ cells having actively entered meiosis is also observed, but it remains to be proved whether the mechanism underlying X-inactivation in the two cases is identical (Lyon 1983). The process of X-inactivation has been somewhat arbitarily divided into three phases: initiation, spreading, and maintenance. Most theories of initiation suggest it is triggered by a developmental cue at strictly programmed specific stages of embryogenesis in the female and spermatogenesis in the male. In the female mouse, X-inactivation first occurs in the trophoectoderm and extraembryonic endoderm at 3.5–4.5 days of gestation. This is followed by the X-inactivation of the tissues of the embryo itself, which occurs at the egg cylinder stage, between days 5.5 and 6.0 of gestation, around the time of uterine implantation (for review, see Epstein 1983; Lyon 1983). The developmental cue that triggers inactivation is thought to be associated with the presence of a “blocking signal” that is produced in limited quantity and binds to a single X chromosome per diploid cell, protecting it from inactivation. Implicit in this model is the idea that prior to, or during, the initial phases of inactivation some sort of counting mechanism is capable of sensing the number of X chromosomes in relation to the autosomal chromosome complement. There is no evidence that this “sensing” is necessarily direct, and it has...
H-2 substitutions on the B6 and AKR backgrounds have been found to decrease allograft resistance ... more H-2 substitutions on the B6 and AKR backgrounds have been found to decrease allograft resistance to the embryonal carcinoma cell line F9. (C57BL/6 x B6.AK-H-2k)F1 and (C57BL/6 x AKR.B6-H-2b)F1 animals show resistance intermediate to that of the respective parental strains and this result, along with that from F2 analyses, suggests that the resistance differential in each congenic pair is under the control of a single semidominant locus. In the C57BL/6 congenic pair, the locus has been shown to lie outside of the H-2, Qua2/3, PGK-2 region of the 17th chromosome.
By using linkage disequilibrium (LD) analysis in 21 strains of known susceptibility to lung cance... more By using linkage disequilibrium (LD) analysis in 21 strains of known susceptibility to lung cancer and by assembling a YAC contig, we mapped to a ∼1.5-Mb region on distal mouse chromosome 6 the Pas1locus, the major determinant of lung cancer predisposition in mice. Our results, on the basis of haplotype and phenetic analysis, suggest that the Pas1s susceptibility allele is shared by several mouse-inbred strains of independent origin, which show either high or intermediate predisposition to lung tumorigenesis. Therefore, the Pas1s allele is probably derived from an ancestral mouse rather than from independent mutations of the same gene. We showed the feasibility of LD in common inbred strains for the fine mapping of disease loci, and provided the biological basis and the reagents for the cloning of the Pas1 gene.
Type 1 diabetes (T1D) is a major disease affecting primarily young children with an incidence in ... more Type 1 diabetes (T1D) is a major disease affecting primarily young children with an incidence in Western societies of around 0.3% by 20 years of age. Although both genetic and environmental factors contribute to the disease aetiology, the precise nature of both the genetic and environmental contribution to human disease onset and progression remains poorly defined. Despite showing some differences from human T1D, rodent models for T1D (Leiter and von Herrath, 2004; von Herrath and Nepom, 2009) and, in particular the nonobese diabetic (NOD) mouse (Atkinson and Leiter, 1999; Kikutani and Makino, 1992), have provided important insights into the disease process, even if they have not yet allowed definitive identification of many of the genetic factors involved in the process. The recent isolation of germline-competent embryonic stem (ES) cells from the NOD mouse strain, and from the rat, will greatly facilitate the functional analysis of T1D in the mouse, and open up the possibility of ...
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