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Let-7 miRNAs 对 Irs2 的抑制对于端脑神经上皮的内稳态至关重要。

Repression of Irs2 by let-7 miRNAs is essential for homeostasis of the telencephalic neuroepithelium.

机构信息

Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas & Universidad Miguel Hernández, Sant Joan d'Alacant, Spain.

CRTD-Center for Regenerative Therapies, School of Medicine, Technische Universität Dresden, Dresden, Germany.

出版信息

EMBO J. 2020 Nov 2;39(21):e105479. doi: 10.15252/embj.2020105479. Epub 2020 Sep 28.

DOI:10.15252/embj.2020105479
PMID:32985705
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7604626/
Abstract

Structural integrity and cellular homeostasis of the embryonic stem cell niche are critical for normal tissue development. In the telencephalic neuroepithelium, this is controlled in part by cell adhesion molecules and regulators of progenitor cell lineage, but the specific orchestration of these processes remains unknown. Here, we studied the role of microRNAs in the embryonic telencephalon as key regulators of gene expression. By using the early recombiner Rx-Cre mouse, we identify novel and critical roles of miRNAs in early brain development, demonstrating they are essential to preserve the cellular homeostasis and structural integrity of the telencephalic neuroepithelium. We show that Rx-Cre;Dicer mouse embryos have a severe disruption of the telencephalic apical junction belt, followed by invagination of the ventricular surface and formation of hyperproliferative rosettes. Transcriptome analyses and functional experiments in vivo show that these defects result from upregulation of Irs2 upon loss of let-7 miRNAs in an apoptosis-independent manner. Our results reveal an unprecedented relevance of miRNAs in early forebrain development, with potential mechanistic implications in pediatric brain cancer.

摘要

胚胎干细胞巢的结构完整性和细胞内稳态对于正常组织发育至关重要。在大脑的神经上皮中，这部分受到细胞黏附分子和祖细胞谱系调节剂的控制，但这些过程的具体协调仍然未知。在这里，我们研究了 microRNAs 在胚胎大脑中的作用，它们是基因表达的关键调节剂。通过使用早期重组酶 Rx-Cre 小鼠，我们发现了 microRNAs 在早期大脑发育中的新的和关键作用，证明它们对于维持大脑神经上皮的细胞内稳态和结构完整性是必需的。我们发现，Rx-Cre;Dicer 小鼠胚胎的大脑顶区连接带严重破坏，随后脑室面内陷并形成过度增殖的玫瑰花结。转录组分析和体内功能实验表明，这些缺陷是由于 let-7 microRNAs 缺失导致 Irs2 上调引起的，这与细胞凋亡无关。我们的结果揭示了 microRNAs 在早期前脑发育中的前所未有的重要性，这可能对小儿脑癌的发生机制具有重要意义。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/414f/7604626/41a985448788/EMBJ-39-e105479-g011.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/414f/7604626/c8ff531bbe0e/EMBJ-39-e105479-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/414f/7604626/18e73124c97d/EMBJ-39-e105479-g010.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/414f/7604626/41a985448788/EMBJ-39-e105479-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/414f/7604626/7c46811fea0d/EMBJ-39-e105479-g003.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/414f/7604626/2e95c05010c9/EMBJ-39-e105479-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/414f/7604626/afad92d8db04/EMBJ-39-e105479-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/414f/7604626/c8ff531bbe0e/EMBJ-39-e105479-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/414f/7604626/18e73124c97d/EMBJ-39-e105479-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/414f/7604626/29b7957babb9/EMBJ-39-e105479-g012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/414f/7604626/9dbc7275db1d/EMBJ-39-e105479-g013.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/414f/7604626/41a985448788/EMBJ-39-e105479-g011.jpg

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