Loss- and gain-of-function mutations show a polycomb group function for Ring1A in mice

Development, Dec 2000

M. del Mar Lorente, C. Marcos-Gutierrez, C. Perez, J. Schoorlemmer, A. Ramirez, T. Magin, M. Vidal

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Loss- and gain-of-function mutations show a polycomb group function for Ring1A in mice

Mara del Mar Lorente 2 3 5 Camelia Marcos-Gutirrez 2 3 5 Claudia Prez 1 2 3 5 Jon Schoorlemmer 2 3 5 Angel Ramrez 0 2 5 Thomas Magin 2 4 5 Miguel Vidal ) 2 3 5 0 Cell and Molecular Biology , CIEMAT, Avda. Complutense, 28040 Madrid, Spain 1 Department of Animal Pathology: Animal Medicine, Faculty of Veterinary Science, University of Len , 24071 Len, Spain 2 Key words: Polycomb, Mouse, Ring1A, Ring1B, Hox, Axial skeleton 3 Developmental and Cell Biology, Centro de Investigaciones Biolgicas , Velzquez 144, 28006 Madrid, Spain 4 Department of Molecular Biology, Institute for Genetics, University of Bonn , Rmerstrasse 164, Bonn 53117, Germany 5 M. del Mar Lorente and others SUMMARY The products of the Polycomb group (PcG) of genes act as transcriptional repressors involved in the maintenance of homeotic gene expression patterns throughout development, from flies to mice. Biochemical and molecular evidence suggests that the mouse Ring1A gene is a member of the PcG of genes. However, genetic evidence is needed to establish PcG function for Ring1A, since contrary to all other murine PcG genes, there is no known Drosophila PcG gene encoding a homolog of the Ring1A protein. To study Ring1A function we have generated a mouse line lacking Ring1A and mouse lines overexpressing Ring1A. Both Ring1A- /- and Ring1A+/- mice show anterior transformations and other abnormalities of the axial The Polycomb group (PcG) of genes were first identified as trans-acting regulators of homeotic gene function in Drosophila (Kennison, 1995). Two clusters of homeotic genes, the Antennapedia complex (ANT-C) and the bithorax complex (BX-C), collectively referred to as the homeotic complex (HOM-C) are responsible for the determination of segmental identities in Drosophila. The ANT-C genes determine and maintain the identity of the head and anterior thoracic segments, whereas the BX-C genes control the identity of posterior thoracic and abdominal segments (Kaufman et al., 1980; Lewis, 1978). The expression of homeotic genes in specific overlapping domains along the anterior-posterior (AP) axis of the embryo is correlated with the physical order of genes in the chromosome (Harding et al., 1985; Lewis, 1978). This principle of colinearity has been conserved in vertebrates (Duboule and Doll, 1989; Graham et al., 1989). Loss- and gain-of-function mutations in the HOM-C genes cause the cells in those regions where the concentration of the homeotic products is altered, to form structures characteristic of a different segment of the fly. One of these homeotic phenotypes is the transformation of the second and third legs into first leg, as is evident from the presence in the second and third legs of skeleton, which indicates an unusual sensitivity of axial skeleton patterning to Ring1A gene dosage. Ectopic expression of Ring1A also results in dose-dependent anterior transformations of vertebral identity, many of which, interestingly, are shared by Ring1A- /- mice. In contrast, the alterations of Hox gene expression observed in both type of mutant mice are subtle and involve a reduced number of Hox genes. Taken together, these results provide genetic evidence for a PcG function of the mouse Ring1A gene. adult males of ectopic sex combs characteristics of the first leg. Mutations in loci outside the HOM-C that cause an extra sex combs phenotype identify the PcG of genes (Jrgens, 1985). In PcG mutants, the initial pattern of expression of HOM-C genes is normal, but later in development a generalized derepression occurs (Simon et al., 1992; Soto et al., 1995; Struhl and Akam, 1985). Thus, the PcG genes function to maintain, rather than to determine, homeotic gene repression. The maintenance of homeotic gene expression is controlled by another set of genes, the trithorax group (trxG), often identified as suppressors of the PcG-induced homeotic phenotypes (Kennison, 1993). The PcG genes encode a group of structurally heterogenous proteins (Simon, 1995). Recently, plant and vertebrate genes encoding proteins containing regions of homology with Drosophila PcG products have been identified (Gould, 1997; Preuss, 1999; Schumacher and Magnuson, 1997). Mutations in these genes result in homeotic phenotypes and alterations in the expression patterns of homeotic genes (Gould, 1997; Schumacher and Magnuson, 1997). This indicates a conservation of the PcG function throughout evolution. The PcG proteins form large complexes arising from their mutual interactions through evolutionary conserved protein motifs (Kyba and Brock, 1998a,b). The genetic interactions and dosage effects of PcG genes in Drosophila (Adler et al., 1991; Cheng et al., 1994; Jrgens, 1985) and in mammals (Bel et al., 1998) agree with PcG function being mediated by multiprotein complexes. Studies in Drosophila have shown that PcG silencing occurs through Polycomb response elements (PRE), which are regulatory DNA sequences harboring in vivo binding sites for PcG proteins (Orlando et al., 1998; Strutt (...truncated)


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M. del Mar Lorente, C. Marcos-Gutierrez, C. Perez, J. Schoorlemmer, A. Ramirez, T. Magin, M. Vidal. Loss- and gain-of-function mutations show a polycomb group function for Ring1A in mice, Development, 2000, pp. 5093-5100, 127/23,