Purkinje cell degeneration in mice lacking the xeroderma pigmentosum groupG gene

Laboratory mice carrying the nonfunctional xeroderma pigmentosum group G ge ne (the mouse counterpart of the human XPG gene) alleles have been generate d by using gene-targeting and embryonic stem cell technology. Homozygote an imals of this autosomal recessive disease exhibited signs and symptoms, suc h as postnatal growth retardation, reduced levels of activity, progressive ataxia and premature death, similar to the clinical manifestations of Cocka yne syndrome (CS). Histological analysis of the cerebellum revealed multipl e pyknotic cells in the Purkinje cell layer of the xpg homozygotes, which h ad atrophic cell bodies and shrunken nuclei. Further examination by an immu nohistochemistry Mr calbindin-D 28k (CaBP) showed that a large number of im munoreactive Purkinje cells were atrophic and their dendritic trees were sm aller and shorter than in wild-type littermates. These results indicated a marked degeneration of Purkinje cells in the xpg mutant cerebellum. Study b y in situ detection of DNA fragmentation in the cerebellar cortex demonstra ted that some deoxynucleotidyl transferase (TdT)mediated dUTP-biotin in sit u nick labeling (TUNEL) positive cells appeared in the granule layer of the mutant mice, but few cell deaths were confirmed in the Purkinje layer. The se results suggested Purkinje cell degeneration in the mutant cerebellum wa s underway, in which much Purkinje cell death had not appeared, and the app earance of some abnormal cerebellar symptoms in the xpg-deficient mice was not only due to a marked Purkinje cell degeneration, but also to damage of other cells. (C) 2001 Wiley-Liss, Inc.