Evidence for the transneuronal regulation of cerebellin biosynthesis in developing Purkinje cells

We have investigated the expression of a unique class of neuropeptides, the cerebellins, in normal and neurodevelopmentally mutant mice. Employing HPLC separation, gas-phase Edman sequencing, and immunocytochemistry, the normal Balb/c mouse cerebellum is shown to contain 2 Purkinje cell-specific neuropeptides, cerebellin and des-Ser1-cerebellin. In this strain of mouse the cerebellins appear during early postnatal development and their subsequent levels parallel the most dramatic period of cerebellar development: granule cell migration and parallel fiber formation, synaptogenesis, Purkinje cell dendritic maturation, and establishment of adult cytoarchitecture. In mutant mice (reeler, weaver, and staggerer), in which these early developmental events are markedly disrupted, Purkinje cells contain much lower levels of cerebellin and des-Ser1-cerebellin. In general there is a correlation between the formation and number of parallel fiber-Purkinje cell synapses and cerebellin levels. For example, the staggerer mutant, which totally lacks these synapses, is essentially devoid of cerebellin, whereas in reeler, cerebellin seems to be dependent upon the position of individual Purkinje cells and their ability to form contacts with granule cells. These results indicate that granule cells can modulate the level of cerebellin in Purkinje cells. A number of models to explain these data are discussed.