| First Author | Bronson RT | Year | 1995 |
| Journal | Mouse Genome | Volume | 93 |
| Issue | 1 | Pages | 152-154 |
| Mgi Jnum | J:24233 | Mgi Id | MGI:71982 |
| Citation | Bronson RT, et al. (1995) Short papers: Acute cerebral neuronal necrosis in copper deficient offspring of female mice with the toxic milk mutation. Mouse Genome 93(1):152-154 |
| abstractText | Full text of Mouse Genome contribution: ACUTE CEREBRAL NEURONAL NECROSIS IN COPPER DEFICIENT OFFSPRING OF FEMALE MICE WITH THE TOXIC MILK MUTATION. Roderick T. Bronson, Hope 0. Sweet, and Muriel T. Davisson The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA Toxic milk (tx) is a recessively inherited mutation first described by Rauch in 1983. Adult mutants are characterized by accumulation of excessive copper in the liver, which eventually leads to cirrhosis(1). In this respect the murine disease resembles Wilson's disease of humans(3) and Bedlington terriers(8). The disease in mice is also expressed as a failure of secretion of copper in the milk, so that newborn offspring of toxic milk dams develop poorly, have poorly pigmented hair, and die by 2 weeks of age, regardless of their own genotype. It is this aspect of the disease that was first noted and gave rise to the mutant's name(14). As might be expected, pups of mutant dams cross-fostered onto normal dams develop normally, and recent work has shown that the copper deficiency in these pups does not affect the expression of the metallothionein-I gene(10). Hitherto no one has described pathologic lesions in affected pups. In this report we describe cerebral cortical necrosis in these animals. The mice studied were from a strain carrying an independent remutation to tx discovered at The Jackson Laboratory, Bar Harbor, Maine. The remutation txJ occurred in the inbred C3H/HeJ strain in 1987(16). The infant mice had the pale coat color, curly whiskers and early mortality characteristic of tx14. Direct tests for allelism proving that txJ was a remutation to tx were conducted for us by Dr. Rauch at the University of Massachusetts, Amherst. Further studies showed that infant mice born to txJ/txJ dams could be rescued by cross fostering on normal dams prior to 14 days of age and older homozygous recessive mice were shown to develop the cirrhosis characteristic of the tx/tx mutant(l). Moreover, txJ/txJ mice had the interesting characteristic seen in tx/tx mice, that the severity of the disease in the pups of any particular dam decreased with each subsequent litter. Thirty two moribund 2 to 3-week-old pups born to homozygous txJ/txJ dams and heterozygous or wild type sires and nursed by their biological mothers were anesthetized with tribromoethanol (Avertin, Aldrich Chemical Co., Milwaukee, WI) and fixed by intracardiac perfusion with formol-acid-alcohol or Bouin's fixatives after a flush of the vasculature with physiological saline. Cross sections of paraffin-embedded brain at the levels of the caudate nucleus, thalamus, midbrain and cerebellum were prepared and stained with hematoxylin and eosin (H & E) or with luxol fast blue and cresylecht violet (LFB-CV). One brain was serially sectioned and stained with LFB-CV. Sections of other major organs -- including liver, heart, kidney and spleen -- from 7 of the animals were also prepared and stained with H & E. Both males and females were studied. The basic lesion in all affected mice was acute neuronal necrosis characterized by nuclear pyknosis and eosinophilia with shrinkage of the cytoplasm (Figs. 1,2). In most mice the necrosis was confined to the dorsal and lateral aspects of the frontal parietal and occipital lobes; the temporal lobe was always spared. Within any section of cortex, layer one and two tended to be spared; necrosis was most severe in layers three to six. Along the length of the cortex the necrosis tended to be distributed in a patchy fashion. Thus, while the dorsal-lateral cortex was badly affected, the more medial and ventral lateral portions of the cortex were normal in some sections and necrotic in others. In some animals the frontal cortex was more severely affected than the occipital; in others the necrosis was more uniformly distributed. In three mice there were patches of necrosis bilaterally in the caudal thalamus. Elsewhere in the diencephalon, hind brain and cerebellum there was no evidence of necrosis. No lesions were present in any other organ. Copper deficiency causes white matter necrosis in lambs, kids and piglets born to dams consuming food stocks grown on copper deficient soils(15). The deficiency in these species is designated Òsway back" and "enzootic ataxia", and often is present at birth. Under some conditions affected animals are born with cerebellar necrosis and cerebral edema. It has been presumed that the pathologic changes are due to defects in respiratory enzymes, since copper is a coenzyme of cytochrome oxidase(15). The pathologic manifestation of copper deficiency in offspring of tx/tx mice differs from that of food animals in that the cerebral cortex, rather than white matter, is primarily affected. In this respect tx/tx mice are similar to adult rats, which develop areas of cerebral necrosis resembling infarcts when fed a copper deficient diet(2). Figure 1. (Legend) Cerebral cortex of 1 week old pup from a tx/tx dam. The leptomeninges are at the top of the figure. There are numerous acutely necrotic neurons in the third cortical layer, demarcated by arrows. H & E. Figure 2. (Legend) High power view of Figure 1, cerebral cortex of 1 day old pup from a tx/tx dam. Pyknotic neuronal nuclei within vacuoles are admixed with more normal neurons. H & E. Toxic milk is a model of Wilson's disease, which maps to human Chr 13q14-q21 9. The location of the Wilson's Disease homolog in the mouse has not yet been reported. This mutant has already been useful in studies of abnormal copper storage(l, 10-13). It can also be used to study the effects of deficient copper on neonatal developing brain, since paradoxically, pups born to dams that store excessive copper are themselves copper deficient, due to inadequate copper in the mother's milk. The toxic milk mutation should be compared with mice homozygous or hemizygous for one or another of the several alleles at the X-linked mottled (Mo) locus. These mice are also copper deficient(7) and are considered to be a model of Menkes' disease. Neurological changes have been reported in Mobr (brindled) males which die within the first week of life(4,5). We have seen acutely necrotic cerebral neurons in young male Mobr mice dying at 2 weeks of age. Wilson's and Menkes' diseases are both mutations in members of an ATPase gene family(6). Acknowledgments This work was supported by NSF grant BIR89-15728 and NIH Cancer Core grant CA34196 (RTB, HOS, MTD). References 1. Biempica, L., Rauch, H., Quintana, N., Sternlieb, I. (1988) Lab. Invest. 59:500-508. 2. Carlton, W.W., Kelly. W.A. (1969) J. Nutr. 97:42-52. 3. Danks, D.M. (1983) The Metabolic Basis of Inherited Disease, 5th ed., pp. 1251-1268. McGraw Hill, New York, New York. 4. Falconer, D.S. (1953) Z Indukt Abstamrnungs Vererbungsl 85: 210-219. 5. Falconer, D.S. (1956) Mouse News Lett. 15:24. 6. GDB, Human Genome Database, maintained at The Johns Hopkins University, December, 1994. 7. Green, M.C. (1989) Catalog of Mutant Genes and Polymorphic Loci, pp. 241-244. In Genetic Variants and Strains of the Laboratory Mouse, eds., M.F. Lyon and A.G. Searle, 2nd ed., Oxford University Press, Oxford. 8. Johnson. G.F.. Gilbertson. S.R.. Goldfischer, S., Grushoff. P.S.. Sternlieb. I. (1984) Vet. Pathol. 21:57. 9. Houwen, R.H.J., Scheffer, H., te Meerman, G.J., van der Vlies, P., Buys, C.H.C.M. (1990) Hum. Genet. 85:560-562. 10. Mann, J.R., Camakaris, J., Francis, N., Danks, D.M. (1981) Biochem. J. 196:81. 11. Mercer, J.F.B., Grimes, A., Danks, D.M., Rauch, H. (1991) J. Nutr. 121:894-899. 12. Mercer, J.F.B., Grimes, A., Rauch, H. (1992) J. Nutr. 122:1254-1259. 13. Phillips, M., Camakaris, J., Danks, D.M. (1991) Biol. Trace Element Res. 29: 11-29. 14. Rauch, H. (1983) J. Hered. 74:141-144. 15. Sullivan, N.D. (1985) Pathology of Domestic Animals vol. 1, 3rd.ed., pp. 202-320. Academic Press, New York, New York. 16. Sweet, H.O., Davisson, M.T. (1989) Mouse News Lett. 84:89. |
