Xiao J, Gong S, Ledoux M S
University of Tennessee Health Science Center, Departments of Neurology and Anatomy and Neurobiology, Memphis, TN 38163, USA.
Neuroscience. 2007 Jan 19;144(2):439-61. doi: 10.1016/j.neuroscience.2006.09.042. Epub 2006 Nov 7.
The genetically dystonic (dt) rat, an autosomal recessive model of generalized dystonia, harbors an insertional mutation in Atcay. As a result, dt rats are deficient in Atcay transcript and the neuronally-restricted protein caytaxin. Previous electrophysiological and biochemical studies have defined olivocerebellar pathways, particularly the climbing fiber projection to Purkinje cells, as sites of significant functional abnormality in dt rats. In normal rats, Atcay transcript is abundantly expressed in the granular and Purkinje cell layers of cerebellar cortex. To better understand the consequences of caytaxin deficiency in cerebellar cortex, differential gene expression was examined in dt rats and their normal littermates. Data from oligonucleotide microarrays and quantitative real-time reverse transcriptase-PCR (QRT-PCR) identified phosphatidylinositol signaling pathways, calcium homeostasis, and extracellular matrix interactions as domains of cellular dysfunction in dt rats. In dt rats, genes encoding the corticotropin-releasing hormone receptor 1 (CRH-R1, Crhr1) and plasma membrane calcium-dependent ATPase 4 (PMCA4, Atp2b4) showed the greatest up-regulation with QRT-PCR. Immunocytochemical experiments demonstrated that CRH-R1, CRH, and PMCA4 were up-regulated in cerebellar cortex of mutant rats. Along with previous electrophysiological and pharmacological studies, our data indicate that caytaxin plays a critical role in the molecular response of Purkinje cells to climbing fiber input. Caytaxin may also contribute to maturational events in cerebellar cortex.
遗传性肌张力障碍（dt）大鼠是全身性肌张力障碍的常染色体隐性模型，其Atcay基因存在插入突变。因此，dt大鼠缺乏Atcay转录本和神经元特异性蛋白caytaxin。先前的电生理和生化研究已确定橄榄小脑通路，特别是攀缘纤维向浦肯野细胞的投射，是dt大鼠显著功能异常的部位。在正常大鼠中，Atcay转录本在小脑皮质的颗粒层和浦肯野细胞层中大量表达。为了更好地理解caytaxin缺乏在小脑皮质中的后果，我们检测了dt大鼠及其正常同窝仔鼠的差异基因表达。来自寡核苷酸微阵列和定量实时逆转录聚合酶链反应（QRT-PCR）的数据确定磷脂酰肌醇信号通路、钙稳态和细胞外基质相互作用是dt大鼠细胞功能障碍的领域。在dt大鼠中，编码促肾上腺皮质激素释放激素受体1（CRH-R1，Crhr1）和质膜钙依赖性ATP酶4（PMCA4，Atp2b4）的基因在QRT-PCR中上调最为显著。免疫细胞化学实验表明，CRH-R1、CRH和PMCA4在突变大鼠的小脑皮质中上调。结合先前的电生理和药理学研究，我们的数据表明caytaxin在浦肯野细胞对攀缘纤维输入的分子反应中起关键作用。Caytaxin也可能有助于小脑皮质的成熟过程。
