The UTX gene escapes X inactivation in mice and humans

We recently have identified a ubiquitously transcribed mouse Y chromosome gene, Uty , which encodes a tetratricopeptide repeat (TPR) protein. A peptide derived from the UTY protein confers H-Y antigenicity on male cells. Here we report the characterization of a widely transcribed X-linked homologue of Uty , called Utx , which maps to the proximal region of the mouse X chromosome and which detects a human X-linked homologue at Xp11.2. Given that Uty is ubiquitously transcribed, we assayed for Utx expression from the inactive X chromosome (Xi) in mice and found that Utx escapes X chromosome inactivation. Only Smcx and the pseudoautosomal Sts gene on the mouse X chromosome have been reported previously to escape inactivation. The human UTX gene was also found to be expressed from Xi. We discuss the significance of these data for our understanding of dosage compensation of X-Y homologous genes in humans and mice.      

Tissue and lineage-specific variation in inactive X chromosome expression of the murine Smcx gene

To understand how gene expression patterns are established on the inactive X chromosome during development, we have studied the murine gene Smcx, which is expressed from both the active and inactive mouse X chromosomes. In all tissues assayed, Smcx only partially escapes X inactivation, with expression levels from the inactive X allele approximately 30-65% that of the active X allele. Additionally, inactive X expression levels differed between extraembryonic and embryonic tissues and among different tissues from newborn and adult mice. Imprinted extraembryonic tissue had the lowest levels of inactive X Smcx expression, whereas the highest levels were in heart. These data suggest that the chromosomal basis of X inactivation differs among tissues, perhaps reflecting differences in the timing or regulation of inactivation in these cell lineages.      

Induced recruitment of NK cells to lymph nodes provides IFN-gamma for T(H)1 priming

Naive T cells are stimulated by antigen-presenting dendritic cells (DCs) in secondary lymphoid organs, but whether other types of cell participate in T cell priming is unclear. Here we show in mice that natural killer (NK) cells, which are normally excluded from lymph nodes, are rapidly recruited in a CCR7-independent, CXCR3-dependent manner to lymph nodes on stimulation by the injection of mature DCs. Recruitment of NK cells is also induced by some, but not all, adjuvants and correlates with the induction of T helper cell type 1 (T(H)1) responses. NK cell depletion and reconstitution experiments show that NK cells provide an early source of interferon-gamma (IFN-gamma) that is necessary for T(H)1 polarization. Taken together, our results identify an induced pathway of NK cell migration in antigen-stimulated lymph nodes and a mechanism by which some adjuvants may facilitate T(H)1 responses.     

Evidence for a change in the expression of beta2-microglobulin-assoicated membrane structures on leukaemic human cells.

Cell-associated and serum beta2-microglobulin was estimated in seven patients with chronic lymphocytic leukaemia. The amount of cell-associated beta2-microglobulin was significantly reduced (P less than 0.01), due to a decrease in the fraction of beta2-microglobulin that passes unretarded through a concanavalin A affinity column (presumably non-HLA-associated beta2-microglobulin). Serum concentrations of beta2-microglobulin were increased, but no correlation was found between the decrease in cell-associated beta2-microglobulin and the increase in serum beta2-microglobulin. All of the beta2-microglobulin from leukaemic serum was eluted corresponding to a molecular weight of 11,800 and none of it was retarded on a concanavalin A affinity column. The decrease in cell-associated beta2-microglobulin might reflect a change in the qualitative or quantitative expression of beta2-microglobulin-associated membrane structures on the leukaemic cells, perhaps conferring resistance to the cells against hypothetical immunological host defence mechanisms.     

RECOMBINATION FRACTIONS IN THE HLA SYSTEM BASED ON THE DATA SET ‘PROVINCES FRANÇAISES’: INDICATIONS OF HAPLOTYPE-SPECIFIC RECOMBINATION RATES

In the large genetic survey ‘Provinces Françaises’ the recombination fractions in the HLA system have been estimated by a family analysis programme (FAP). A total of 1332 families were analysed and in general the findings were in agreement with recombination fractions reported previously. The maternal recombination rates were on average 1.8 times higher than the corresponding ones for males. The comparison of the recombination fractions with the corresponding physical distances suggests the existence of hot spots of recombination. The analysis did not show deviations from expected values for HLA-A and B alleles on HLA-A/B recombinant haplotypes. However, analysis of HLA-B/DR recombinant haplotypes showed a skewed distribution of B and DR alleles. The significance of the findings is difficult to evaluate as all results are estimated numbers and frequencies but a manual analysis of the recombinant families confirmed the observations. HLA-B/DR recombinant haplotypes carried often HLA-DR3 and DR11 whereas DR2 and DR7 were more rarely present on recombinant haplotypes. DR4 had an increased incidence on BF/DR recombinant haplotypes but not on A/B or B/BF recombinant haplotypes. Some of the haplotypes with the strongest linkage disequilibria as A1, B8, DR3 and A3, B7, DR2 seem to be less frequently involved in recombinations than other haplotypes. Variations of recombination rates depending on certain alleles or haplotypes might partially explain the conservation of some haplotypes or part of haplotypes in Caucasoids.     

The mouse Mid1 gene: implications for the pathogenesis of Opitz syndrome and the evolution of the mammalian pseudoautosomal region

We have recently reported isolation of the gene responsible for X- linked Opitz G/BBB syndrome, a defect of midline development. MID1 is located on the distal short arm of the human X chromosome (Xp22. 3) and encodes a novel member of the B box family of zinc finger proteins. We have now cloned the murine homolog of MID1 and performed preliminary expression studies during development. Mid1 expression in undifferentiated cells in the central nervous, gastrointestinal and urogenital systems suggests that abnormal cell proliferation may underlie the defect in midline development characteristic of Opitz syndrome. We have also found that Mid1 is located within the mouse pseudoautosomal region (PAR) in Mus musculus , while it seems to be X- specific in Mus spretus. Therefore, Mid1 is likely to be a recent acquisition of the M. musculus PAR. Genetic and FISH analyses also demonstrated a high frequency of unequal crossovers in the murine PAR, creating spontaneous deletion/duplication events involving Mid1. These data provide evidence for the first time that genetic instability of the PAR may affect functionally important genes. In addition, we show that MID1 is the first example of a gene subject to X-inactivation in man while escaping it in mouse. These data contribute to a better understanding of the molecular content and evolution of the rodent PAR.      

Influence of synchronous and sequential stimulation on muscle fatigue

In acute experiments the sciatic nerve of the rat is electrically stimulated to induce fatigue in the medial Gastrocnemius muscle. Fatigue tests are carried out using intermittent stimulation of different compartments (sequential) or a single compartment (synchronous) of the sciatic nerve. The activation of different compartments is achieved by dividing nerve fibres into subbundles and placing them in separate grooves in a multigroove electrode. The aim of the investigation is to quantify the effect of sequential contra synchronised stimulation in reducing muscle fatigue, with no overlap between compartments. Overlap between two compartments is calculated using the combined and individual forces from both compartments. Sequential stimulation of two and three compartments is investigated. There is a significant decrease of fatigue in sequential stimulation compared to synchronous. After 2 min of intermittent stimulation the force time level is significantly increased in sequential stimulation, than in synchronous stimulation. The rate of force time decrease is significantly slower in sequential stimulation than in synchronous stimulation. With sequential stimulation it takes significantly longer before the maximal force time is reached than with synchronous stimulation.     

Über die Verteilung von Radiostrontium in den Organen eines menschlichen Feten

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