Clark B R, LaRegina M, Tolbert D L
Program in Physical Therapy, Washington University School of Medicine, Campus Box 8502, 4444 Forest Park Blvd., St. Louis, MO 63108, USA.
Brain Res. 2000 Mar 10;858(2):264-73. doi: 10.1016/s0006-8993(99)02415-4.
This study reports on the mode of inheritance of the shaker mutation and the development of an inbred strain of the shaker rat mutation from Sprague Dawley outbred stock onto a Wistar Furth background. Neuroanatomical and behavioral expression of the affected phenotype, through seven generations of backcross and intercross breeding, has confirmed the mode of inheritance to be X-linked. Behaviorally, affected mutants present with a wide-based ataxic gait and whole body tremor. In affected mutants calbindin immunostaining for surviving cerebellar Purkinje cells revealed widespread degeneration in the anterior lobe and in limited areas of the posterior lobe. Fast Fourier transform analysis of the tremor revealed a frequency of 3-5 Hz. As predicted by X-linked inheritance, female descendants of an affected male are carriers for the genotype and the phenotype is expressed in one-half of her male offspring. There was spatially random and limited degeneration of Purkinje cells in carrier females, but they did not display overt clinical signs of ataxia and tremor. These data provide further support for using the shaker mutant rat as an animal model for studies of mechanisms underlying human heredodegenerative diseases.
本研究报告了摇椅突变的遗传模式，以及从斯普拉格·道利远交原种培育出的摇椅大鼠突变近交系在Wistar Furth背景上的培育过程。通过七代回交和杂交育种，对受影响表型的神经解剖学和行为学表现进行研究，证实其遗传模式为X连锁。行为上，受影响的突变体表现出宽基共济失调步态和全身震颤。对存活的小脑浦肯野细胞进行钙结合蛋白免疫染色，发现受影响的突变体在前叶和后叶有限区域存在广泛的退化。对震颤进行快速傅里叶变换分析，结果显示频率为3 - 5Hz。正如X连锁遗传所预测的那样，受影响雄性的雌性后代为该基因型的携带者，且其表型在其一半的雄性后代中表达。在携带者雌性中，浦肯野细胞存在空间上随机且有限的退化，但它们并未表现出明显的共济失调和震颤临床症状。这些数据为将摇椅突变大鼠用作研究人类遗传性退行性疾病潜在机制的动物模型提供了进一步支持。
