FEZ1-mediated axonal transport plays important roles in central nervous system development but its involvement in the peripheral nervous system is not well-characterized. FEZ1 is deleted in Jacobsen syndrome (JS), an 11q terminal deletion developmental disorder. JS patients display impaired psychomotor skills, including gross and fine motor delay, suggesting that FEZ1 deletion may be responsible for these phenotypes, given its association with the development of motor-related circuits. Supporting this hypothesis, our data show that FEZ1 is selectively expressed in the rat brain and spinal cord. Its levels progressively increase over the developmental course of human motor neurons (MN) derived from embryonic stem cells. Deletion of FEZ1 strongly impaired axon and dendrite development, and significantly delayed the transport of synaptic proteins into developing neurites. Concurring with these observations, Drosophila unc-76 mutants showed severe locomotion impairments, accompanied by a strong reduction of synaptic boutons at neuromuscular junctions. These abnormalities were ameliorated by pharmacological activation of UNC-51/ATG1, a FEZ1-activating kinase, with rapamycin and metformin. Collectively, the results highlight a role for FEZ1 in MN development and implicate its deletion as an underlying cause of motor impairments in JS patients.

中文翻译：

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雅各布森综合征中缺失的基因 FEZ1 的缺失通过损害运动神经元发育导致运动缺陷和早期死亡

FEZ1 介导的轴突运输在中枢神经系统发育中起重要作用，但其在周围神经系统中的参与尚不明确。FEZ1在 Jacobsen 综合征 (JS) 中被删除，这是一种 11q 末端缺失发育障碍。JS 患者表现出精神运动技能受损，包括粗大和精细运动延迟，这表明FEZ1缺失可能是导致这些表型的原因，因为它与运动相关回路的发展有关。支持这一假设，我们的数据显示 FEZ1 在大鼠脑和脊髓中选择性表达。它的水平在源自胚胎干细胞的人类运动神经元 (MN) 的发育过程中逐渐增加。删除FEZ1轴突和树突发育严重受损，并显着延迟了突触蛋白向发育中的神经突的转运。与这些观察结果一致，果蝇 unc-76突变体表现出严重的运动障碍，伴随着神经肌肉接头处突触 boutons 的强烈减少。这些异常通过 UNC-51/ATG1（一种 FEZ1 激活激酶）与雷帕霉素和二甲双胍的药理学激活得到改善。总的来说，结果突出了 FEZ1 在 MN 发展中的作用，并暗示其缺失是 JS 患者运动障碍的根本原因。