Deregulation of Neuro-Developmental Genes and Primary Cilium Cytoskeleton Anomalies in iPSC Retinal Sheets from Human Syndromic Ciliopathies
Deregulation of Neuro-Developmental Genes and Primary Cilium Cytoskeleton Anomalies in iPSC Retinal Sheets from Human Syndromic Ciliopathies
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DOI：
10.1016/j.stemcr.2020.02.005
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发表时间：
2020-03-10
影响因子：
5.9
通讯作者：
Bernier, Gilbert
中科院分区：
文献类型：
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作者：
Barabino, Andrea;Flamier, Anthony;Bernier, Gilbert
纤毛病是影响初级纤毛结构和功能的异质性遗传疾病。Meckel-Gruber（MKS）和Bardet-Biedl（BBS）综合征是以骨骼和神经发育异常为特征的严重纤毛病，包括多指（趾）畸形、认知障碍和视网膜变性。我们描述了人诱导多能干细胞（iPSC）衍生的视网膜片（RS）的产生和分子特征，这些视网膜片来自对照组、MKS（TMEM 67）和BBS（BBS 10）病例。MKS和BBS RS在数百个发育基因和WNT和BMP途径成员的表达中显示出显著的共同改变。晶状体蛋白分子伴侣的诱导在MKS和BBS RS中是突出的，这表明对错误折叠的蛋白质的应激反应。独特的MKS光感受器是存在额外的中心粒和纤毛，纤毛蛋白的聚集。BBS光感受器的独特之处在于DNA损伤的积累和有丝分裂纺锤体检查点的激活。这项研究揭示了如何结合细胞重编程，器官发生和下一代测序，使参与人类纤毛病变的机制阐明。
Ciliopathies are heterogeneous genetic diseases affecting primary cilium structure and function. Meckel-Gruber (MKS) and Bardet-Biedl (BBS) syndromes are severe ciliopathies characterized by skeletal and neurodevelopment anomalies, including polydactyly, cognitive impairment, and retinal degeneration. We describe the generation and molecular characterization of human induced pluripotent stem cell (iPSC)-derived retinal sheets (RSs) from controls, and MKS (TMEM67) and BBS (BBS10) cases. MKS and BBS RSs displayed significant common alterations in the expression of hundreds of developmental genes and members of the WNT and BMP pathways. Induction of crystallin molecular chaperones was prominent in MKS and BBS RSs suggesting a stress response to misfolded proteins. Unique to MKS photoreceptors was the presence of supernumerary centrioles and cilia, and aggregation of ciliary proteins. Unique to BBS photoreceptors was the accumulation of DNA damage and activation of the mitotic spindle checkpoint. This study reveals how combining cell reprogramming, organogenesis, and next-generation sequencing enables the elucidation of mechanisms involved in human ciliopathies.