Differential regulation of bcl-2, bax, c-fos, junB, and krox-24 expression in the cerebellum of Purkinje cell degeneration mutant mice.
Purkinje cell degeneration (pcd) is an autosomal recessive mutation in the mouse characterized by an almost complete loss of cerebellar Purkinje neurons between postnatal days 22 and 28. The pcd gene has not been identified, however, a relationship between activation of specific genes and cell death has been suggested in other models of neuronal cell death. In the present study we analyzed the expression of several candidate cell death effector genes (bax, c-fos, junB, krox-24) and a cell death repressor gene (bcl-2) in the cerebellum of pcd homozygotes and wild-type mice. At postnatal day 22, when Purkinje cells start to degenerate, levels of c-fos, junB, and krox-24 mRNA increased about 5-fold in mutants. To the contrary, the amount of bcl-2 mRNA declined and bax transcripts remained unchanged compared to wild-type animals. Immunoreactivity for c-Fos and Jun could be detected exclusively in cerebellar Purkinje neurons of pcd mice but not in wild-types, whereas the number of Bcl-2 immunopositive Purkinje cells decreased significantly in mutants. Both double labeling experiments and immunostaining of consecutive sections revealed lack of colocalization of Jun with Bcl-2. These results demonstrate an induction of members of the fos and jun family and a downregulation of antiapoptotic bcl-2 in cerebellar Purkinje neurons that are destined to die. Fos and Jun transcription factor proteins may be implicated in the regulation of bcl-2 expression and in the signal cascade leading to Purkinje cell death.
Gillardon
F
F
Universität Heidelberg, II. Physiologisches Institut, Germany.
Bäurle
J
J
Wickert
H
H
Grüsser-Cornehls
U
U
Zimmermann
M
M
D000818:Animals; D001483:Base Sequence; D002531:Cerebellum / Q000473:pathology / Q000503:physiopathology*; D004268:DNA-Binding Proteins / Q000235:genetics*; D051766:Early Growth Response Protein 1; D005786:Gene Expression Regulation; D017874:Immediate-Early Proteins; D051379:Mice; D008818:Mice, Neurologic Mutants; D008969:Molecular Sequence Data; D009410:Nerve Degeneration; D015345:Oligonucleotide Probes / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D011689:Purkinje Cells / Q000473:pathology*; D014157:Transcription Factors / Q000235:genetics*
D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D017874:Immediate-Early Proteins; D015345:Oligonucleotide Probes; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors