Pafah1b2 mutations suppress the development of hydrocephalus in compound Pafah1b1; Reln and Pafah1b1; Dab1 mutant mice
Pafah1b2 mutations suppress the development of hydrocephalus in compound Pafah1b1; Reln and Pafah1b1; Dab1 mutant mice
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DOI：
10.1016/j.neulet.2008.04.096
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发表时间：
2008-07-04
影响因子：
2.5
通讯作者：
D'Arcangelo, Gabriella
中科院分区：
文献类型：
--
作者：
Assadi, Amir H.;Zhang, Guangcheng;D'Arcangelo, Gabriella
Reelin是一种通过Dab1衔接蛋白发出信号的细胞外蛋白，Lis1调节脑中的神经元迁移和细胞层形成。在小鼠或人类中，Reelin的缺失和Lis1活性的降低导致皮质结构的紊乱。Pafah1b1基因的产物Lis1与Alpha1（Pafah1b3基因的产物）和Alpha2（Pafah1b2基因的产物）结合形成Pafah1b异源三聚体复合物。这种复合物与Reelin途径在生物化学和遗传学上相互作用，然而，Alpha1和Alpha2在大脑发育中的作用知之甚少。我们以前证明了Pafah1b1与Reelin通路基因的复合突变导致双突变小鼠的分层缺陷和脑积水的出现。在这里，我们产生三重小鼠突变体，以研究单个Pafah1b α亚基对细胞层形成和脑积水的影响。我们发现，Pafah1b3突变加剧分层缺陷，而Pafah1b2突变强烈抑制复合突变小鼠的脑积水表型。这些数据表明，两个Pafah1b2 α亚基对大脑发育有着截然不同的影响，并以显著不同的方式与Reelin信号通路相互作用。(c)2008爱思唯尔爱尔兰有限公司保留所有权利。
Reelin, an extracellular protein that signals through the Dab1 adapter protein, and Lis1 regulate neuronal migration and cellular layer formation in the brain. Loss of Reelin and reduction in Lis1 activity in mice or humans results in the disorganization of cortical structures. Lis1, the product of the Pafah1b1 gene associates with Alphal (the product of the Pafah1b3 gene) and Alpha2 (the product of the Pafah1b2 gene) to form the Pafah1b heterotrimeric complex. This complex interacts biochemically and genetically with the Reelin pathway, however, the role of Alphal and Alpha2 in brain development is poorly understood. We previously demonstrated that compound mutations of Pafah1b1 with genes in Reelin pathway result in layering defects and the appearance of hydrocephalus in double mutant mice. Here, we generate triple mouse mutants to investigate the effect of individual Pafah1b Alpha subunits on cellular layer formation and hydrocephalus. We found that Pafah1b3 mutations exacerbate the layering defects, whereas Pafah1b2 mutations strongly suppress the hydrocephalus phenotype of compound mutant mice. The data indicate that the two Pafah1b2 Alpha subunits have profoundly different effects on brain development and interact in a significantly different manner with the Reelin signaling pathway. (c) 2008 Elsevier Ireland Ltd. All rights reserved.