Guénette Suzanne, Chang Yang, Hiesberger Thomas, Richardson James A, Eckman Christopher B, Eckman Elizabeth A, Hammer Robert E, Herz Joachim
Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Charlestown, MA 02129-4404, USA.
EMBO J. 2006 Jan 25;25(2):420-31. doi: 10.1038/sj.emboj.7600926. Epub 2006 Jan 12.
Targeted deletion of two members of the FE65 family of adaptor proteins, FE65 and FE65L1, results in cortical dysplasia. Heterotopias resembling those found in cobblestone lissencephalies in which neuroepithelial cells migrate into superficial layers of the developing cortex, aberrant cortical projections and loss of infrapyramidal mossy fibers arise in FE65/FE65L1 compound null animals, but not in single gene knockouts. The disruption of pial basal membranes underlying the heterotopias and poor organization of fibrillar laminin by isolated meningeal fibroblasts from double knockouts suggests that FE65 proteins are involved in basement membrane assembly. A similar phenotype is observed in triple mutant mice lacking the APP family members APP, APLP1 and APLP2, all of which interact with FE65 proteins, suggesting that this phenotype may be caused by decreased transmission of an APP-dependent signal through the FE65 proteins. The defects observed in the double knockout may also involve the family of Ena/Vasp proteins, which participate in actin cytoskeleton remodeling and interact with the WW domains of FE65 proteins.
衔接蛋白FE65家族的两个成员FE65和FE65L1的靶向缺失会导致皮质发育异常。在FE65/FE65L1复合基因敲除动物中会出现类似于鹅卵石样无脑回畸形中所见的异位，即神经上皮细胞迁移到发育中皮质的表层，同时出现异常的皮质投射和锥体下苔藓纤维缺失，但在单基因敲除动物中未出现。双敲除动物分离出的脑膜成纤维细胞导致异位下方软脑膜基底膜破坏以及纤维状层粘连蛋白组织紊乱，这表明FE65蛋白参与基底膜组装。在缺乏APP家族成员APP、APLP1和APLP2的三突变小鼠中观察到类似的表型，所有这些成员都与FE65蛋白相互作用，这表明该表型可能是由于APP依赖信号通过FE65蛋白的传递减少所致。双敲除中观察到的缺陷也可能涉及Ena/Vasp蛋白家族，该家族参与肌动蛋白细胞骨架重塑并与FE65蛋白的WW结构域相互作用。
