The Robotic Mouse: Understanding the Role of AF4, a Cofactor of Transcriptional Elongation and Chromatin Remodelling, in Purkinje Cell Function
The Robotic Mouse: Understanding the Role of AF4, a Cofactor of Transcriptional Elongation and Chromatin Remodelling, in Purkinje Cell Function
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DOI：
10.1007/s12311-009-0101-0
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发表时间：
2009-09-01
期刊：
影响因子：
3.5
通讯作者：
Davies, Kay E.
中科院分区：
文献类型：
--
作者：
Bitoun, Emmanuelle;Davies, Kay E.
神经系统疾病占全世界疾病负担的很大一部分，随着预期寿命的延长，与年龄有关的疾病的发病率将继续上升。基因靶向已经并将继续是产生临床相关小鼠模型的有价值的方法，从而阐明潜在的分子基础。然而，由于大多数这些条件的病因仍然是未知的，现在正在使用基于大规模随机化学诱变的反向方法，试图识别控制神经元细胞死亡和存活的新基因和相关信号通路。在这里，我们回顾了一种新的常染色体显性遗传性小脑共济失调模型的特点，它显示了一般的生长迟缓，并开发成人发病的区域特异性浦肯野细胞丢失以及白内障和缺陷的早期T细胞成熟。我们先前已经确定，突变的蛋白Af 4，这是一个成员的AF 4/LAF 4/FMR 2（ALF）家族的转录辅因子经常易位在儿童白血病，经历较慢的蛋白酶体周转通过泛素途径和异常积累在小脑浦肯野细胞。我们还表明，Af 4的功能作为一个大的多蛋白复合物的一部分，刺激RNA聚合酶II的延伸和介导的染色质重塑在转录过程中。随着即将确定的基因靶点，触发浦肯野细胞死亡的机器人小脑，和ALF蛋白之间的功能保守，机器人小鼠有望提供重要的见解人类共济失调的发病机制，但也与FMR 2和LAF 4有关的精神发育迟滞。
Neurological disorders represent a large share of the disease burden worldwide, and the incidence of age-related forms will continue to rise with life expectancy. Gene targeting has been and will remain a valuable approach to the generation of clinically relevant mouse models from which to elucidate the underlying molecular basis. However, as the aetiology of the majority of these conditions is still unknown, a reverse approach based on large-scale random chemical mutagenesis is now being used in an attempt to identify new genes and associated signalling pathways that control neuronal cell death and survival. Here, we review the characterisation of a novel model of autosomal dominant cerebellar ataxia which shows general growth retardation and develops adult-onset region-specific Purkinje cell loss as well as cataracts and defects in early T-cell maturation. We have previously established that the mutated protein Af4, which is a member of the AF4/LAF4/FMR2 (ALF) family of transcription cofactors frequently translocated in childhood leukaemia, undergoes slower proteasomal turnover through the ubiquitin pathway and abnormally accumulates in Purkinje cells of the cerebellum. We have also shown that Af4 functions as part of a large multiprotein complex that stimulates RNA polymerase II elongation and mediates chromatin remodelling during transcription. With the forthcoming identification of the gene targets that trigger Purkinje cell death in the robotic cerebellum, and the functional conservation among the ALF proteins, the robotic mouse promises to deliver important insights into the pathogenesis of human ataxia, but also of mental retardation to which FMR2 and LAF4 have been linked.