Albrecht U, Abu-Issa R, Rätz B, Hattori M, Aoki J, Arai H, Inoue K, Eichele G
Department of Biochemistry, Baylor College of Medicine, Houston, Texas 77030, USA.
Dev Biol. 1996 Dec 15;180(2):579-93. doi: 10.1006/dbio.1996.0330.
A hemizygous deletion of LIS1, the gene encoding alphaLis1 protein, causes Miller-Dieker syndrome (MDS). MDS is a developmental disorder characterized by neuronal migration defects resulting in a disorganization of the cerebral and cerebellar cortices. alphaLis1 binds to two other proteins (beta and gamma) to form a heterotrimeric cytosolic enzyme which hydrolyzes platelet-activating factor (PAF). The existence of heterotrimers is implicated from copurification and crosslinking studies carried out in vitro. To determine whether such a heterotrimeric complex could be present in tissues, we have investigated whether the alphaLis1, beta, and gamma genes are coexpressed in the developing and adult brain. We have isolated murine cDNAs and show by in situ hybridization that in developing brain tissues alphaLis1, beta, and gamma genes are coexpressed. This suggests that alphaLis1, beta, and gamma gene products form heterotrimers in developing neuronal tissues. In the adult brain, alphaLis1 and beta mRNAs continue to be coexpressed at high levels while gamma gene expression is greatly diminished. This reduction in gamma transcript levels is likely to result in a decline of the cellular concentration of alphaLis1, beta, and gamma heterotrimers. The developmental expression pattern of alphaLis1, beta, and gamma genes is consistent with the neuronal migration defects seen in MDS; regions containing migrating neurons such as the developing cerebral and cerebellar cortices express these genes at a particularly high level. Furthermore, we uncovered a correlation between gamma gene expression, granule cell migration, and PAF hydrolytic activity in the cerebellum. In this tissue gamma gene expression and PAF hydrolysis peaked at Postnatal Days P5 and P15, a period during which neuronal migration in the cerebellum is most extensive. Mechanisms by which PAF could affect neuronal migration are discussed.
编码αLis1蛋白的基因LIS1发生半合子缺失会导致米勒-迪克尔综合征（MDS）。MDS是一种发育障碍，其特征是神经元迁移缺陷，导致大脑和小脑皮质结构紊乱。αLis1与另外两种蛋白质（β和γ）结合形成一种异源三聚体细胞质酶，该酶可水解血小板活化因子（PAF）。体外进行的共纯化和交联研究表明存在异源三聚体。为了确定这种异源三聚体复合物是否可能存在于组织中，我们研究了αLis1、β和γ基因在发育中的大脑和成年大脑中是否共表达。我们分离出了小鼠cDNA，并通过原位杂交表明，在发育中的脑组织中，αLis1、β和γ基因共表达。这表明αLis1、β和γ基因产物在发育中的神经元组织中形成异源三聚体。在成年大脑中，αLis1和β mRNA继续高水平共表达，而γ基因表达则大大减少。γ转录水平的这种降低可能导致αLis1、β和γ异源三聚体的细胞浓度下降。αLis1、β和γ基因的发育表达模式与MDS中所见的神经元迁移缺陷一致；含有迁移神经元的区域，如发育中的大脑和小脑皮质，这些基因的表达水平特别高。此外，我们发现小脑γ基因表达、颗粒细胞迁移和PAF水解活性之间存在相关性。在该组织中，γ基因表达和PAF水解在出生后第5天和第15天达到峰值，这是小脑神经元迁移最广泛的时期。文中讨论了PAF影响神经元迁移的机制。
