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Non-Random X-Chromosome Inactivation in Mouse X-Autosome Translocation Embryos—Location of the Inactivation Centre

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Non-Random X-Chromosome Inactivation in Mouse X-Autosome Translocation Embryos—Location of the Inactivation Centre J. Embryol. exp. Morph. 78, 1-22 (1983) Printed in Great Britain (E) The Company of Biologists Limited 1983 Non-random X-chromosome inactivation in mouse X-autosome translocation embryos—location of the inactivation centre By SOHAILA RASTAN1 From the Division of Comparative Medicine, Clinical Research Centre, Harrow SUMMARY X-chromosome inactivation was investigated cytologically using the modified Katida method which differentially stains inactive X-chromosome material at metaphase in balanced 13|-day female embryos heterozygous for four X-autosome rearrangements, reciprocal trans- locations T(X;4)37H, T(X;11)38H and T(X;16)16H (Searle's translocation) and the insertion translocation Is(7;X)lCt (Cattanach's translocation). In all cases non-random inactivation was found. In the reciprocal translocation heterozygotes only one translocation product ever showed Kanda staining. In addition in a proportion of cells from T(X;4)37H, T(X;11)38H &nd Is(7;X)lCt the Kanda staining revealed differential staining of X-chromosome material and attached autosomal material within the translocation product. In a study of 8£-day female embryos doubly heterozygous for Searle's translocation and Cattanach's translocation two unbalanced types of embryo were found. In one type of unbalanced female embryo of the karyotype 40(X(7)/X16;16/16) no inactivated X- chromosomal material is found. A second unbalanced type of female embryo, of the presump- tive karyotype 40(X(7)/XN;16x/l6) was found in which two inactivated chromosomes were present in the majority of metaphase spreads. A simple model for the initiation of X- chromosome inactivation based on the presence of a single inactivation centre distal to the breakpoint in Searle's translocation explains these findings. INTRODUCTION Chromosomal rearrangements between the X chromosome and the auto- somes interrupt the physical continuity of the X chromosome and are thus of use in the study of both the randomness and mechanisms of X-inactivation. One property of X-autosome translocations is the spread of inactivation into autosomal loci attached to the X chromosome analogous to position-effect variegation in Drosophila (Baker, 1971; Cattanach, 1974; Russell & Mont- gomery, 1970). Female mice which are heterozygous for X-autosomal transloca- tions and carry marker genes which are recessive in the relevant autosomes exhibit a variegated phenotype due to spreading of inactivation into attached autosomal material in cells where the translocated X chromosome is inactive. 1 Author's address: Division of Comparative Medicine, Clinical Research Centre, Watford Road, Harrow, Middlesex HA1 3UJ, U.K. 2 S. RASTAN To date 14 X-autosome translocations have been reported in the mouse (reviewed by Eicher, 1970 and Searle, 1981). X-autosome rearrangements are often characterized by non-random X-inactivation. This could be the result of initial random X-inactivation followed by selection for cells with the maximum genetic balance or the result of primary non-random X-inactivation caused by a disturbance in the process of X-inactivation due to rearranged control centres. There is ample evidence that cell selection does operate in the two cell popula- tions generated by random X-inactivation, for example in the female mule and hinny (Giannelli & Hamerton, 1971; Hamerton et al. 1971; Hook & Brustman, 1971; Cohen & Rattazzi, 1972), in heterozygotes for certain X-autosome aberra- tions in mouse and man (Cattanach, 1975; Disteche, Eicher & Latt, 1979; Russell & Cacheiro, 1978) and in blood cell populations of women heterozygous for X-linked hypoxanthine phosphoribosyl transferase deficiency (Nyhan et al. 1970). The data on inactivation centres are less clear cut. Various models for the initiation of X-inactivation have been proposed based on either the concept of a single inactivation centre on the X chromosome (e.g. Russell & Cacheiro, 1978) or more than one inactivation centre (e.g. Eicher, 1970; Disteche, Eicher & Latt, 1981). Previous work on balanced carriers of various reciprocal X- autosome translocations in the mouse suggest that only one translocation product is ever inactivated in cells in which the normal X is active (Russell & Montgomery, 1965, 1970). In particular in the autoradiographic studies of Russell & Cacheiro (1978) in which late replication was used as evidence of inactivation in cells from adults and 18-day embryos heterozygous for six independent translocations T(X;7)2R1, T(X;7)3R1, T(X;7)5R1, T(X;7)6R1, T(X;4)1R1 and T(X;4)7R1 it was found that in each case the shorter transloca- tion product was never late-labelling in any cell. These results support the con- cept of a single inactivation centre from which inactivation is able to spread in both directions. However the inactivation of both parts of an X chromosome divided by an autosomal insertion such as in Is(X;7)lCt (Cattanach's transloca- tion) has been used to support the concept of at least two inactivation centres (Eicher, 1970). Searle's translocation (T(X;16)16H) is of particular interest in the study of the mechanism of X-inactivation as it is the only X-autosome translocation in the mouse described to date that has the breakpoint in the X in a more or less central position. It is also characterized by marked nonrrandom inactivation. Heterozygous females behave as if the normal X is completely inactive in all cells. All X-linked mutant genes located on either part of the translocated X behave as if dominant, without variegation in the heterozygote (Lyon, 1966; Lyon, Searle, Ford & Ohno, 1964). In a cytogenetic study using Budr (5-Bromo- 2'-deoxyuridine) labelling Takagi (1980) reported that in balanced Searle's translocation heterozygotes at 6-5 days most cells had the normal X chromosome inactivated. He also found an unbalanced carrier embryo of the karyotype 40(XN/X16;16/16) which did not show any asynchronously replicating Non-random X-chromosome inactivation in mouse embryos 3 chromosome in any cell, despite the fact that inactivation of the X16 translocation product (containing the centromeric portion of the X) would have restored genetic balance. He concluded that the X16 product was incapable of being inactivated due to lack of an -inactivation centre and also" suggested that the concurrence of at least two X-chromosome loci separated by the breakpoint in Searle's translocation was necessary for the homologous X to be inactivated. In conflict with these results is the report by Disteche et al. (1981) using Budr labelling in balanced female Searle's translocation heterozygotes that in adult bone marrow and in 9-day embryos respectively, 7 % and 1 % of cells had the X16 product late replicating. This has been used to support the concept of at least two inactivation centres on the X chromosome. The studies reported here were designed to obtain further data on this controversy using the modified Kanda method (1973), (Rastan, Kaufman, Handyside & Lyon, 1980; Rastan, 1981) for differential dark staining of the inactive X chromosome, on female embryos heterozygous for the reciprocal translocations T(X;4)37H, T(X;11)38H and T(X;16)16H (Searle's transloca- tion) and the insertion Is(7;X)lCt (Cattanach's translocation). MATERIALS AND METHODS X-autosomal translocations (for review see Searle, 1981) T(X;4)37H (Fig. 1A). A reciprocal translocation between the X and chromosome 4 to give long and short somatic marker chromosomes. The trans- location will be hereafter abbreviated to T37H. T(X;11)38H (Fig. IB). A reciprocal translocation between the X and chromosome 11 which gives long and short somatic markers. The translocation will be hereafter abbreviated to T38H. Is(7;X)lCt (see Fig. 1C). This translocation involves an inverted piece of chromosome 7 inserted into the X to produce a long somatic marker. The trans- location occurs as two types, Type I, balanced, with the inserted X and a deleted chromosome 7, and Type II with the inserted piece of chromosome 7 present as a duplication (Cattanach, 1974). Unlike carriers of the other X-autosome trans- locations males of both types can be fertile. In this study only Type II (i.e. unbalanced duplication form) females and males were used. The translocation will be hereafter abbreviated to IslCt. T(X;16)16H (see Fig. ID). A reciprocal translocation between the X and chromosome 16. The longer translocation product with the centromeric segment of the X (X16) corresponds roughly in length to the intact X, and the shorter translocation product with the centromeric segment of chromosome 16 (16X), to the intact chromosome 16 (Eicher, Nesbitt & Francke, 1972). The translocation will be hereafter abbreviated to T16H. S. RASTAN T37H T38H ft spf wa-2 spf wi vt b m Ta Ta Gy Gy TICt D T16H X16 spf spf Bn Ta Gy Mo c P ru-2 Gy Fig. 1. Relative cytological lengths of the various translocations: (A) T(X;4)37H, (B) T(X;11)38H, (C) Is(7;X)lCt (Cattanach's translocation) and (D) T(X,16)16H (Searle's translocation). Embryos Embryos heterozygous for the various X-autosome translocations were produced by mating spontaneously ovulating females heterozygous for T37H, Non-random X-chromosome inactivation in mouse embryos 5 T38H and IslCt to normal Fi males of the 3H1 strain (Fi between two inbred strains 101/H and C3H/HeH). The Xce status of the translocated Xes have not been characterized; however the X chromosome of the 3HI males is known to carry Xce?. For T16H/+ heterozygous embryos, as the translocation products are not sufficiently different in size from a normal X chromosome or a normal chromosome 16 to be morphologically distinguishable, embryos doubly heterozygous for T16H and IslCt were produced to facilitate distinguishing between X chromosomes. This was achieved by mating spontaneously ovulating T16H/+ females to fertile Type II IslCt males.
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