INTRODUCTION In humans, genetic deficiency of the enzyme hypoxanthine phosphoribosyl transferase (HPRT; EC 2.4.2.8), which is encoded by a gene on the X chromosome, causes Lesch- Nyhan syndrome (reviewed by Stout and Caskey, 1989). Lesch-Nyhan patients show a characteristic group of behav- ioural abnormalities, including spastic cerebral palsy, choreoathetosis and compulsive selfmutilation. It has been proposed that at least some of these abnormalities result from a deficiency in the dopamine-mediated pathways of the basal ganglia of the brain, since 70-90% depletion of dopamine was seen in all three Lesch-Nyhan patients autopsied by Lloyd et al. (1981) and reduced dopamine metabolite levels have been reported in the cerebrospinal fluid of Lesch-Nyhan patients throughout life (Silverstein et al., 1983). As well as these behavioural abnormalities, effects on haematopoiesis are also present. In different studies, megaloblastic anaemia, macrocytic and mega- loblastic changes, haemolytic anaemia and subnormal pop- ulations of B lymphocytes have been reported (reviewed by Stout and Caskey, 1989). In heterozygous female carriers, where X-chromosome inactivation produces a mixture of functionally HPRT + and HPRT - cells, there is strong selection against the HPRT - population in haematopoietic tissues, to the extent that this population is undetectable in adult lymphocytes and erythrocytes (Dancis et al., 1968; McDonald and Kelley, 1972). However, in three young female heterozygotes (7 to 17 years old), between 5 and 10% of lymphocytes were HPRT deficient, suggesting that the extent of selection is age dependent (Albertini and De Mars, 1974). We and others have produced mice deficient in HPRT by breeding from germ-line chimaeras generated by blastocyst injection of HPRT-deficient embryonal stem cells (Hooper et al., 1987; Kuehn et al., 1987). These mice do not show the behavioural abnormalities of the human condition (Finger et al., 1988; Hooper, 1988). Trauma to the ears and flanks caused by overgrooming has been seen in some old HPRT-deficient mice, but it remains to be established whether this is due to the mutation (Williamson et al., 1992). There is a significant reduction in dopamine levels in the basal ganglia, but the extent of the reduction is much smaller than in human patients (Finger et al., 1988; Dunnett et al., 1989; Williamson et al., 1991). Recent work suggests that HPRT deficiency has less severe neurological and behav- ioural consequences in mice than in humans because mice are more reliant on adenine phosphoribosyl transferase (APRT) than HPRT for purine salvage (Wu and Melton, 1993). 859 Development 118, 859-863 (1993) Printed in Great Britain © The Company of Biologists Limited 1993 The basis of a previously observed difference in the level of contribution of hypoxanthine phosphoribosyltrans- ferase-deficient cells between the haematopoietic and non-haematopoietic tissues of chimaeric and heterozy- gous mice has been clarified by studying two populations of female mice that differ only in that one is heterozy- gous for a null allele at the hprt locus and the other is wild type at this locus. Both populations are heterozy- gous for an electrophoretic variant allele at the X-linked Pgk-1 locus, so that X-chromosome inactivation generates cells expressing different isozymes of phos- phoglycerate kinase which can be assayed to monitor cell selection. The results show that hypoxanthine phospho- ribosyltransferase deficiency itself, rather than an effect of another X-linked gene, causes a reduced level of con- tribution to haematopoietic tissues. Further, the extent of the depletion increases significantly with age, and this effect is due to a progressive reduction in the level of con- tribution to haematopoietic tissues rather than to an increase in the level of contribution to non-haematopoi- etic tissues. Key words: haematopoiesis, HPRT, Lesch-Nyhan syndrome SUMMARY Age-dependent selection against hypoxanthine phosphoribosyl transferase-deficient cells in mouse haematopoiesis K. Samuel 1 , A. R. Clarke 2 , J. D. Ansell 1,3 and M. L. Hooper 2,3, * 1 Institute of Cell, Animal and Population Biology, Ashworth Laboratories, University of Edinburgh, West Mains Road, Edinburgh EH9 3JT, UK 2 Cancer Research Campaign Laboratories, Department of Pathology, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK 3 AFRC Centre for Genome Research, King’s Buildings, University of Edinburgh, West Mains Road, Edinburgh EH9 3JQ, UK *Author for correspondence at address 2