Guo Y, Livne-Bar I, Zhou L, Boulianne G L
Program in Developmental Biology, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
J Neurosci. 1999 Oct 1;19(19):8435-42. doi: 10.1523/JNEUROSCI.19-19-08435.1999.
Presenilins are a highly conserved family of proteins first identified as causative genes in early onset familial Alzheimer's disease. Recent studies have suggested a role for presenilins in the Notch-signaling pathway, but their specific function within this pathway remains unclear. Here, we have characterized the Drosophila presenilin gene and protein and studied their interaction with Notch in both mutants and transgenics. We find that the Drosophila presenilin protein is proteolytically cleaved and broadly expressed during development with the highest levels in neurons within the larval CNS. We also show that mutations in Drosophila presenilin (Dps) genetically interact with Notch and result in an early pupal-lethal phenotype characterized by defects in eye and wing development and incomplete neuronal differentiation within the larval CNS. Moreover, we find that processing of Notch in the Golgi by the furin protease is unaffected in Dps mutants and that Notch is present and may even accumulate on the plasma membrane of neuroblasts in the larval CNS of Dps mutants. In contrast, overexpression of Dps in transgenics causes Notch to accumulate in the cytoplasm. Taken together, these results indicate that Drosophila presenilin is required for proper neuronal differentiation and may regulate the subcellular localization of Notch proteins within cells, necessary for their accumulation and subsequent signaling capabilities.
早老素是一类高度保守的蛋白质家族，最初被鉴定为早发性家族性阿尔茨海默病的致病基因。最近的研究表明早老素在Notch信号通路中发挥作用，但其在该通路中的具体功能仍不清楚。在这里，我们对果蝇早老素基因和蛋白质进行了表征，并在突变体和转基因果蝇中研究了它们与Notch的相互作用。我们发现果蝇早老素蛋白在发育过程中被蛋白水解切割，广泛表达，在幼虫中枢神经系统的神经元中表达水平最高。我们还表明，果蝇早老素（Dps）的突变与Notch发生遗传相互作用，导致早期蛹致死表型，其特征为眼睛和翅膀发育缺陷以及幼虫中枢神经系统内神经元分化不完全。此外，我们发现弗林蛋白酶在高尔基体中对Notch的加工在Dps突变体中不受影响，并且Notch存在于Dps突变体幼虫中枢神经系统神经母细胞的质膜上甚至可能在其上积累。相反，转基因果蝇中Dps的过表达导致Notch在细胞质中积累。综上所述，这些结果表明果蝇早老素是正常神经元分化所必需的，并且可能调节细胞内Notch蛋白的亚细胞定位，这对于它们的积累和随后的信号传导能力是必要的。
