Genetic Dissection of Cerebellar Development: Mutations Affecting Cell Position

SYNOPSIS. The spastic mutation induces swimming coordinationand equilibrium deficiencies in the Mexican axolotl (Ambystomamexicanum). Behavioral ontogeny studies determined that spaslksfail to develop behavior trains of sinusoidal flexures necessaryto mediate escape swimming at the time of onset of cerebellarfunction. Behavior analysis, after lesioning different cranialnerve roots and CNS areas in wild-type animals, confirmed the"behavioral focus" of the mutation to lie in the auricle orvestibulo-cerebellum. Single unit recordings in the cerebellarauricle and adjacent brainstem vestibular zone (area acoustico-lateralis)of mutants revealed a full complement of vestibular unit typesfound in wild-type. However, the gene appears to alter the physicallocation of vestibular units in both areas, including a ventral"translocation" of cerebellar units responding to sustainedipsilateral tilt. Correlated with this unit translocation, mutantPurkinje cells and allied afferent tracts are malpositionedventrally, i.e., "crowded" into an ectopic zone in the ventro-posteriorcerebellum. Studies on cerebellar structure at the time of onsetof spasticity (early feeding stage) confirmed the ventral malpositioningof cerebellar cells and fiber tracts seen in adults. In conjunctionwith these larval studies, mutant larvae injected with tritiatedthymidine during early cerebellogenesis and assayed at the earlyfeeding stage revealed a medio-ventral malpositioning of labelledcells; in wild-type, labelled cells were positioned laterally.Interestingly, the neuropathology of the reeler mutation (rev.,Mariani et al., 1977) found in the mouse is remarkably similarto that of the spastic axolotl. Both cerebella are reduced insize, misshapen, and lack fissures. Purkinje cells appear ectopicallyin the granular layer, white matter and deep cerebellar nuclei.Although both cerebella lack structural integrity, no individualcell type shows marked or progressive degeneration, and cellularuntrastructure appears intact; thus, both genes appear to actindependently of the genesis of cerebellar elements. Instead,they appear to influence morphogenetic movements by which presumptivecerebellar cells attain their proper positions during the neurogeneticsequence.