FAILED CELL-MIGRATION AND DEATH OF PURKINJE-CELLS AND DEEP NUCLEAR NEURONS IN THE WEAVER CEREBELLUM

The mouse neurological mutant weaver has an atrophic cerebellar cortex with deficits in both Purkinje and granule cell number. Although gran ule cells are known to die postnatally shortly after their final cell division, the cause of the Purkinje cell deficit (cell death vs lack o f production) is unknown. We report here a quantitative analysis of la rge cerebellar neurons of the weaver mutant during postnatal developme nt. We explored the hypothesis that the cells of the entire cerebellar anlage were affected by the mutation by including in our study the ne urons of the deep cerebellar nuclei (DCN). Our analysis reveals that i n homozygous weaver mutants (1) the DCN are displaced laterally, displ ay an abnormal anatomy, and suffer a 20-25% decrease in neuron number; (2) this numerical deficit is located in medial regions, similar to t he localization of cortical deficits in both Purkinje and granule cell s; (3) pyknotic figures are present in the juvenile DCN and in the Pur kinje cell layer; and (4) the majority of cell death in these populati ons occurs not in medial regions where the numerical deficits are obse rved, but rather laterally where adult cell number is nearly normal. T hese results lead us to propose that the complete weaver phenotype inc ludes a failure of the cell movements that lead to the fusion of the b ilateral cerebellar anlage, and that this failure to migrate properly leaves some of the Purkinje cells and DCN neurons in a position where they are unable to make appropriate connections, leading to their deat h. In addition to implications for normal development, these observati ons suggest that weaver effects on the cerebellum can be unified into one consolidated model in which failure of cell movement affects all m ajor cerebellar neurons.