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Restoration of the defect in radial glial fiber migration and cortical plate organization in a brain organoid model of Fukuyama muscular dystrophy
iScience ( IF 5.8 ) Pub Date : 2021-09-17 , DOI: 10.1016/j.isci.2021.103140
Mariko Taniguchi-Ikeda 1, 2, 3 , Michiyo Koyanagi-Aoi 4, 5, 6 , Tatsuo Maruyama 7 , Toru Takaori 8, 9 , Akiko Hosoya 4, 5, 6 , Hiroyuki Tezuka 10 , Shotaro Nagase 11 , Takuma Ishihara 12 , Taisuke Kadoshima 11 , Keiko Muguruma 13, 14 , Keiko Ishigaki 15 , Hidetoshi Sakurai 8 , Akira Mizoguchi 16 , Bennett G Novitch 17, 18, 19 , Tatsushi Toda 20 , Momoko Watanabe 21, 22 , Takashi Aoi 4, 5, 6
Affiliation  

Fukuyama congenital muscular dystrophy (FCMD) is a severe, intractable genetic disease that affects the skeletal muscle, eyes, and brain and is attributed to a defect in alpha dystroglycan (αDG) O-mannosyl glycosylation. We previously established disease models of FCMD; however, they did not fully recapitulate the phenotypes observed in human patients. In this study, we generated induced pluripotent stem cells (iPSCs) from a human FCMD patient and differentiated these cells into three-dimensional brain organoids and skeletal muscle. The brain organoids successfully mimicked patient phenotypes not reliably reproduced by existing models, including decreased αDG glycosylation and abnormal radial glial (RG) fiber migration. The basic polycyclic compound Mannan-007 (Mn007) restored αDG glycosylation in the brain and muscle models tested and partially rescued the abnormal RG fiber migration observed in cortical organoids. Therefore, our study underscores the importance of αDG O-mannosyl glycans for normal RG fiber architecture and proper neuronal migration in corticogenesis.



中文翻译:

福山肌营养不良脑类器官模型中放射状胶质纤维迁移和皮质板组织缺陷的修复

福山先天性肌营养不良症 (FCMD) 是一种严重的难治性遗传疾病,会影响骨骼肌、眼睛和大脑,并归因于 α 肌营养不良蛋白 (αDG) O的缺陷-甘露糖基化。我们之前建立了 FCMD 疾病模型;然而,他们并没有完全概括在人类患者中观察到的表型。在这项研究中,我们从人类 FCMD 患者中生成了诱导多能干细胞 (iPSC),并将这些细胞分化为三维脑类器官和骨骼肌。脑类器官成功地模仿了现有模型无法可靠再现的患者表型,包括降低的 αDG 糖基化和异常的径向胶质 (RG) 纤维迁移。碱性多环化合物 Mannan-007 (Mn007) 在测试的大脑和肌肉模型中恢复了 αDG 糖基化,并部分挽救了在皮质类器官中观察到的异常 RG 纤维迁移。因此,我们的研究强调了 αDG O的重要性-甘露糖聚糖,用于正常的 RG 纤维结构和皮质生成中的适当神经元迁移。

更新日期:2021-09-29
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