Disruption in murine Eml1 perturbs retinal lamination during early development
Disruption in murine Eml1 perturbs retinal lamination during early development
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DOI：
10.1038/s41598-020-62373-5
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发表时间：
2020-03-27
影响因子：
4.6
通讯作者：
Nishina, P. M.
中科院分区：
文献类型：
--
作者：
Collin, G. B.;Won, J.;Nishina, P. M.
在哺乳动物发育过程中，在哺乳动物中枢神经系统的分层组织中建立功能性神经网络取决于神经元的正确迁移和定位，这一过程称为层压。特别是，视网膜和脑皮质脑室区的假复层神经上皮为祖细胞增殖和迁移提供了平台。这些组织中的层压缺陷会导致神经元错位、神经元连接破坏和功能异常。这些组织中正确层压所需的分子机制尚不完全清楚。在这里，我们在一种新型小鼠模型 tvrm360 中发现了 Eml1 基因的无义突变，该突变表现出皮质下异位、脑积水和视网膜结构紊乱。在视网膜中，Eml1 破坏导致发育早期感光细胞核定位异常。成熟后，这些异位光感受器拥有纤毛并形成突触，但未能产生坚固的外节，这意味着继发于错误定位的光感受器分化的晚期缺陷。此外，穆勒细胞体和双极细胞的异常定位在整个内部神经母细胞层中都很明显。在出生后第 0 天，在 tvrm360 小鼠中观察到视网膜神经上皮中有丝分裂核的基底位移。出生时视网膜祖细胞的异常定位以及成熟时光感受器和次级神经元的异位存在表明 EML1 在眼睛发育早期发挥作用，并且对于细胞增殖和发育过程中适当的视网膜分层至关重要。
During mammalian development, establishing functional neural networks in stratified tissues of the mammalian central nervous system depends upon the proper migration and positioning of neurons, a process known as lamination. In particular, the pseudostratified neuroepithelia of the retina and cerebrocortical ventricular zones provide a platform for progenitor cell proliferation and migration. Lamination defects in these tissues lead to mispositioned neurons, disrupted neuronal connections, and abnormal function. The molecular mechanisms necessary for proper lamination in these tissues are incompletely understood. Here, we identified a nonsense mutation in the Eml1 gene in a novel murine model, tvrm360, displaying subcortical heterotopia, hydrocephalus and disorganization of retinal architecture. In the retina, Eml1 disruption caused abnormal positioning of photoreceptor cell nuclei early in development. Upon maturation, these ectopic photoreceptors possessed cilia and formed synapses but failed to produce robust outer segments, implying a late defect in photoreceptor differentiation secondary to mislocalization. In addition, abnormal positioning of Muller cell bodies and bipolar cells was evident throughout the inner neuroblastic layer. Basal displacement of mitotic nuclei in the retinal neuroepithelium was observed in tvrm360 mice at postnatal day 0. The abnormal positioning of retinal progenitor cells at birth and ectopic presence of photoreceptors and secondary neurons upon maturation suggest that EML1 functions early in eye development and is crucial for proper retinal lamination during cellular proliferation and development.