Maricich S M, Soha J, Trenkner E, Herrup K
Alzheimer Research Laboratory, Department of Neurology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
J Neurosci. 1997 May 15;17(10):3675-83. doi: 10.1523/JNEUROSCI.17-10-03675.1997.
The mouse neurological mutant weaver has an atrophic cerebellar cortex with deficits in both Purkinje and granule cell number. Although granule cells are known to die postnatally shortly after their final cell division, the cause of the Purkinje cell deficit (cell death vs lack of production) is unknown. We report here a quantitative analysis of large cerebellar neurons of the weaver mutant during postnatal development. We explored the hypothesis that the cells of the entire cerebellar anlage were affected by the mutation by including in our study the neurons of the deep cerebellar nuclei (DCN). Our analysis reveals that in homozygous weaver mutants (1) the DCN are displaced laterally, display an abnormal anatomy, and suffer a 20-25% decrease in neuron number; (2) this numerical deficit is located in medial regions, similar to the localization of cortical deficits in both Purkinje and granule cells; (3) pyknotic figures are present in the juvenile DCN and in the Purkinje cell layer; and (4) the majority of cell death in these populations occurs not in medial regions where the numerical deficits are observed, but rather laterally where adult cell number is nearly normal. These results lead us to propose that the complete weaver phenotype includes a failure of the cell movements that lead to the fusion of the bilateral 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 death. In addition to implications for normal development, these observations suggest that weaver effects on the cerebellum can be unified into one consolidated model in which failure of cell movement affects all major cerebellar neurons.
小鼠神经学突变体韦弗（weaver）具有萎缩的小脑皮质，浦肯野细胞和颗粒细胞数量均有缺陷。虽然已知颗粒细胞在出生后最终细胞分裂后不久死亡，但浦肯野细胞缺陷（细胞死亡还是产生不足）的原因尚不清楚。我们在此报告对韦弗突变体出生后发育过程中小脑大神经元的定量分析。我们探讨了这样一种假说，即通过在研究中纳入小脑深部核团（DCN）的神经元，整个小脑原基的细胞都受到了突变的影响。我们的分析表明，在纯合韦弗突变体中：（1）DCN向外侧移位，解剖结构异常，神经元数量减少20 - 25%；（2）这种数量缺陷位于内侧区域，类似于浦肯野细胞和颗粒细胞皮质缺陷的定位；（3）在幼年DCN和浦肯野细胞层中存在固缩核；（4）这些群体中的大多数细胞死亡并非发生在观察到数量缺陷的内侧区域，而是发生在成年细胞数量接近正常的外侧区域。这些结果使我们提出，完整的韦弗表型包括导致双侧小脑原基融合的细胞运动失败，而这种迁移失败使一些浦肯野细胞和DCN神经元处于无法建立适当连接的位置，从而导致它们死亡。除了对正常发育的影响外，这些观察结果表明，韦弗对小脑的影响可以统一到一个综合模型中，即细胞运动失败影响所有主要的小脑神经元。
