Carlson Kerri M, Melcher Laura, Lai Shaojuan, Zoghbi Huda Y, Clark H Brent, Orr Harry T
Institute of Human Genetics, University of Minnesota, Minneapolis, MN 55455, USA.
J Neurogenet. 2009;23(3):313-23. doi: 10.1080/01677060802399976. Epub 2008 Dec 10.
In mammals, ataxin-1 (ATXN1) is a member of a family of proteins in which each member contains an AXH domain. Expansion of the polyglutamine tract in ATXN1 causes the neurodegenerative disease, spinocerebellar ataxia type 1 (SCA1) with prominent cerebellar pathology. Toward a further characterization of the genetic diversification of the ATXN1/AXH gene family, we identified and characterized members of this gene family in zebrafish, a lower vertebrate with a cerebellum. The zebrafish genome encodes two ATXN1 homologs, atxn1a and atxn1b, and one ATXN1L homolog, atxn1l. Key biochemical features of the human ATXN1 protein not seen in the invertebrate homologs (a nuclear localization sequence and a site of phosphorylation at serine 776) are conserved in the zebrafish homologs, and all three zebrafish Atxn1/Axh proteins behave similarly to their human counterparts in tissue-culture cells. Importantly, each of the three homologs is expressed in the zebrafish cerebellum, which in humans, is a prominent site of SCA1 pathogenesis. In addition, atxn1a and atxn1b are expressed in the developing zebrafish cerebellum. These data show that in zebrafish, a lower vertebrate, the complexity of the atxn1/axh gene family is more similar to higher vertebrates than invertebrates with a simple central nervous system and suggests a relationship between the diversification of the ATXN1/AXH gene family and the development of a complex central nervous system, including a cerebellum.
在哺乳动物中，ataxin-1（ATXN1）是一个蛋白质家族的成员，该家族的每个成员都包含一个AXH结构域。ATXN1中多聚谷氨酰胺序列的扩增会导致神经退行性疾病——1型脊髓小脑共济失调（SCA1），其具有明显的小脑病变。为了进一步表征ATXN1/AXH基因家族的遗传多样性，我们在斑马鱼（一种具有小脑的低等脊椎动物）中鉴定并表征了该基因家族的成员。斑马鱼基因组编码两个ATXN1同源物，即atxn1a和atxn1b，以及一个ATXN1L同源物atxn1l。人类ATXN1蛋白的关键生化特征（在无脊椎动物同源物中未发现的核定位序列和丝氨酸776处的磷酸化位点）在斑马鱼同源物中是保守的，并且所有三种斑马鱼Atxn1/Axh蛋白在组织培养细胞中的行为与其人类对应物相似。重要的是，这三种同源物中的每一种都在斑马鱼小脑中表达，而在人类中，小脑是SCA1发病的主要部位。此外，atxn1a和atxn1b在发育中的斑马鱼小脑中表达。这些数据表明，在低等脊椎动物斑马鱼中，atxn1/axh基因家族的复杂性与高等脊椎动物更为相似，而与具有简单中枢神经系统的无脊椎动物不同，这表明ATXN1/AXH基因家族的多样化与包括小脑在内的复杂中枢神经系统的发育之间存在关联。
