ATF6 is essential for human cone photoreceptor development
ATF6 is essential for human cone photoreceptor development
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DOI：
10.1073/pnas.2103196118
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发表时间：
2021-09-28
影响因子：
11.1
通讯作者：
Lin, Jonathan H.
中科院分区：
文献类型：
--
作者：
Kroeger, Heike;Grandjean, Julia M. D.;Lin, Jonathan H.
内质网（ER）应激和未折叠蛋白反应（UPR）信号传导促进了许多人类疾病的病理。UPR调节因子激活转录因子6 （ATF6）的功能丧失变体通过不明确的病理机制导致严重的先天性视力丧失疾病，如色盲。为了研究这一点，我们从携带ATF6疾病变异体的色盲患者诱导的多能干细胞和基因编辑的ATF6缺失hESCs中生成视网膜类器官。我们发现，色盲患者和ATF6缺失视网膜类器官不能形成锥体结构，同时锥体光传导基因表达缺失，而杆状光感受器发育正常。携带ATF6变异的色盲患者的自适应光学视网膜成像也显示锥体内/外段结构缺失，但保留了杆状结构，反映了我们视网膜类器官中观察到的锥体形成缺陷。这些结果表明，ATF6对人类锥体发育至关重要。有趣的是，我们发现一种选择性的小分子ATF6信号激动剂可以恢复一些ATF6致病变异的转录活性，并刺激携带这些变异的患者视网膜类器官的锥体生长和基因表达。这些发现支持ATF6通路的药物靶向可以促进人类视锥细胞的发育，并应进一步探索其在致盲性视网膜疾病中的应用。
Endoplasmic reticulum (ER) stress and Unfolded Protein Response (UPR) signaling promote the pathology of many human diseases. Loss-of-function variants of the UPR regulator Activating Transcription Factor 6 (ATF6) cause severe congenital vision loss diseases such as achromatopsia by unclear pathomechanisms. To investigate this, we generated retinal organoids from achromatopsia patient induced pluripotent stem cells carrying ATF6 disease variants and from gene-edited ATF6 null hESCs. We found that achromatopsia patient and ATF6 null retinal organoids failed to form cone structures concomitant with loss of cone phototransduction gene expression, while rod photoreceptors developed normally. Adaptive optics retinal imaging of achromatopsia patients carrying ATF6 variants also showed absence of cone inner/outer segment structures but preserved rod structures, mirroring the defect in cone formation observed in our retinal organoids. These results establish that ATF6 is essential for human cone development. Interestingly, we find that a selective small molecule ATF6 signaling agonist restores the transcriptional activity of some ATF6 disease-causing variants and stimulates cone growth and gene expression in patient retinal organoids carrying these variants. These findings support that pharmacologic targeting of the ATF6 pathway can promote human cone development and should be further explored for blinding retinal diseases.