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Modeling PTEN overexpression-induced microcephaly in human brain organoids
Molecular Brain ( IF 3.6 ) Pub Date : 2021-08-30 , DOI: 10.1186/s13041-021-00841-3
Navroop Dhaliwal 1 , Wendy W Y Choi 1, 2, 3 , Julien Muffat 1, 2, 4 , Yun Li 1, 2
Affiliation  

The phosphatase and tensin homolog (PTEN) protein, encoded by the PTEN gene on chromosome 10, is a negative regulator of the phosphoinositide 3-kinase (PI3K) signaling pathway. Loss of PTEN has been linked to an array of human diseases, including neurodevelopmental disorders such as macrocephaly and autism. However, it remains unknown whether increased dosage of PTEN can lead to human disease. A recent human genetics study identifies chromosome 10 microduplication encompassing PTEN in patients with microcephaly. Here we generated a human brain organoid model of increased PTEN dosage. We showed that mild PTEN overexpression led to reduced neural precursor proliferation, premature neuronal differentiation, and the formation of significantly smaller brain organoids. PTEN overexpression resulted in decreased AKT activation, and treatment of wild-type organoids with an AKT inhibitor recapitulated the reduced brain organoid growth phenotypes. Together, our findings provide functional evidence that PTEN is a dosage-sensitive gene that regulates human neurodevelopment, and that increased PTEN dosage in brain organoids results in microcephaly-like phenotypes.

中文翻译:

在人脑类器官中模拟 PTEN 过表达诱导的小头畸形

由 10 号染色体上的 PTEN 基因编码的磷酸酶和张力蛋白同源物 (PTEN) 蛋白是磷酸肌醇 3-激酶 (PI3K) 信号通路的负调节因子。PTEN 的缺失与一系列人类疾病有关,包括大头畸形和自闭症等神经发育障碍。然而,增加 PTEN 的剂量是否会导致人类疾病仍然未知。最近的一项人类遗传学研究确定了小头畸形患者中包含 PTEN 的 10 号染色体微重复。在这里,我们生成了增加 PTEN 剂量的人脑类器官模型。我们发现轻度 PTEN 过表达导致神经前体增殖减少、神经元过早分化和明显更小的脑类器官的形成。PTEN 过表达导致 AKT 活化减少,和用 AKT 抑制剂治疗野生型类器官概括了减少的脑类器官生长表型。总之,我们的研究结果提供了功能性证​​据,表明 PTEN 是一种调节人类神经发育的剂量敏感基因,并且脑类器官中 PTEN 剂量的增加会导致类似小头畸形的表型。
更新日期:2021-08-30
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