Function of FEZF1 during early neural differentiation of human embryonic stem cells
Function of FEZF1 during early neural differentiation of human embryonic stem cells
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FEZF1在人胚胎干细胞早期神经分化过程中的功能
DOI：
10.1007/s11427-017-9155-4
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发表时间：
2018-01-01
影响因子：
9.1
通讯作者：
Zhou, Jiaxi
中科院分区：
文献类型：
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作者：
Liu, Xin;Su, Pei;Zhou, Jiaxi
由于缺乏细胞系统和复杂的伦理问题，对人类神经发育机制的理解受到了阻碍。人类胚胎干细胞 (hESC) 具有无限的自我更新能力和分化为人体内几乎所有细胞类型的能力，为剖析人类发育提供了宝贵的模型。在这项研究中，使用化学定义的神经诱导方案和分子分析，我们确定了 Fez 家族锌指 1 (FEZF1) 作为人类早期神经发育的潜在调节剂。 FEZF1 在 hESC 的神经分化过程中迅速上调，并在 PAX6 之前表达，PAX6 是早期人类神经诱导的成熟标志物。我们使用 CRISPR-CAS9 技术生成了 FEZF1 敲除的 H1 hESC 系，发现 FEZF1 的缺失会消除 hESC 的神经分化。此外，FEZF1的缺失会损害hESC在神经特化过程中的多能性退出，这部分解释了FEZF1缺失引起的神经诱导缺陷。然而，FEZF1 本身的强制表达无法驱动 hESC 中的神经分化，这表明 FEZF1 对于 hESC 的神经分化是必要的，但还不够。总而言之，我们的研究结果确定了神经诱导时表达的最早的调节因子之一，并提供了对人类早期神经发育的深入了解。
The understanding of the mechanism underlying human neural development has been hampered due to lack of a cellular system and complicated ethical issues. Human embryonic stem cells (hESCs) provide an invaluable model for dissecting human development because of unlimited self-renewal and the capacity to differentiate into nearly all cell types in the human body. In this study, using a chemical defined neural induction protocol and molecular profiling, we identified Fez family zinc finger 1 (FEZF1) as a potential regulator of early human neural development. FEZF1 is rapidly up-regulated during neural differentiation in hESCs and expressed before PAX6, a well-established marker of early human neural induction. We generated FEZF1-knockout H1 hESC lines using CRISPR-CAS9 technology and found that depletion of FEZF1 abrogates neural differentiation of hESCs. Moreover, loss of FEZF1 impairs the pluripotency exit of hESCs during neural specification, which partially explains the neural induction defect caused by FEZF1 deletion. However, enforced expression of FEZF1 itself fails to drive neural differentiation in hESCs, suggesting that FEZF1 is necessary but not sufficient for neural differentiation from hESCs. Taken together, our findings identify one of the earliest regulators expressed upon neural induction and provide insight into early neural development in human.