SELECTIVE FAILURE OF BRAIN-DERIVED NEUROTROPHIC FACTOR MESSENGER-RNA EXPRESSION IN THE CEREBELLUM OF STARGAZER, A MUTANT MOUSE WITH ATAXIA

In search of the possible involvement of neurotrophic factors in inher ited neurological disease, we examined brain-derived neurotrophic fact or (BDNF), nerve growth factor (NGF), and neurotrophin-3 (NT-3) mRNA e xpression patterns in the ataxic mutant mouse stargazer (stg). Using i n situ hybridization, we found a selective and near total reduction in BDNF mRNA in the cerebellar granule cell layer. NT-3 or NGF mRNA expr ession in the cerebellum was normal. Northern blot analysis demonstrat ed a 70% reduction in BDNF mRNA in the whole cerebellum. BDNF mRNA lev els in other mutant brain regions were unchanged. Absence of BDNF mRNA in granule cells was observed at postnatal age (P15), coincident with the onset of ataxia, and expression levels failed to follow the devel opmental increase found in the wild type at later ages (P20 and P30). Despite the severe BDNF reduction, in situ hybridization patterns for both the full-length and the truncated BDNF TrkB receptor mRNA were un altered. No major cytoarchitectural abnormalities were apparent in the stg/stg cerebellum. BDNF expression in a related ataxic mutant, totte ring, was unaltered. These data show that BDNF can be regulated select ively in distinct brain regions, possibly by differential activation o f its multiple promoters. Absence of cerebellar granule cell BDNF mRNA in stg/stg mice demonstrates that sustained expression of this neurot rophin is not required for cell survival in the developing cerebellar cortex. Our data, in contrast, suggest a role of BDNF in maturation of specific cerebellar neurons and pathways. Early failure of cerebellar BDNF expression may be related to the ataxic phenotype in stg mice.