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IGF2BP1[Formula: see text] 小鼠中标记肌动蛋白 mRNA 失调。

Tagged actin mRNA dysregulation in IGF2BP1[Formula: see text] mice.

出版信息

Proc Natl Acad Sci U S A. 2022 Sep 13;119(37):e2208465119. doi: 10.1073/pnas.2208465119. Epub 2022 Sep 6.

DOI:10.1073/pnas.2208465119
PMID:36067310
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9477413/
Abstract

Gene expression is tightly regulated by RNA-binding proteins (RBPs) to facilitate cell survival, differentiation, and migration. Previous reports have shown the importance of the Insulin-like Growth Factor II mRNA-Binding Protein (IGF2BP1/IMP1/ZBP1) in regulating RNA fate, including localization, transport, and translation. Here, we generated and characterized a knockout mouse to study RBP regulation. We report that IGF2BP1 is essential for proper brain development and neonatal survival. Specifically, these mice display disorganization in the developing neocortex, and further investigation revealed a loss of cortical marginal cell density at E17.5. We also investigated migratory cell populations in the IGF2BP1[Formula: see text] mice, using BrdU labeling, and detected fewer mitotically active cells in the cortical plate. Since RNA localization is important for cellular migration and directionality, we investigated the regulation of -actin messenger RNA (mRNA), a well-characterized target with established roles in cell motility and development. To aid in our understanding of RBP and target mRNA regulation, we generated mice with endogenously labeled -actin mRNA (IGF2BP1[Formula: see text]; -actin-MS2[Formula: see text]). Using endogenously labeled -actin transcripts, we report IGF2BP1[Formula: see text] neurons have increased transcription rates and total -actin protein content. In addition, we found decreased transport and anchoring in knockout neurons. Overall, we present an important model for understanding RBP regulation of target mRNA.

摘要

基因表达受 RNA 结合蛋白 (RBPs) 的严格调控，以促进细胞存活、分化和迁移。先前的报告表明胰岛素样生长因子 II mRNA 结合蛋白 (IGF2BP1/IMP1/ZBP1) 在调节 RNA 命运方面的重要性，包括定位、运输和翻译。在这里，我们生成并表征了一种敲除小鼠来研究 RBP 调控。我们报告 IGF2BP1 对于正常的大脑发育和新生存活率是必不可少的。具体来说，这些小鼠在发育中的新皮质中表现出组织紊乱，进一步的研究表明在 E17.5 时皮质边缘细胞密度丧失。我们还研究了 IGF2BP1[Formula: see text] 小鼠中的迁移细胞群，使用 BrdU 标记，并在皮质板中检测到较少有丝分裂活性的细胞。由于 RNA 定位对于细胞迁移和方向性很重要，我们研究了肌动蛋白信使 RNA (mRNA) 的调节，这是一种具有既定作用的特征靶标细胞迁移和发育。为了帮助我们理解 RBP 和靶标 mRNA 的调控，我们生成了内源标记肌动蛋白 mRNA (IGF2BP1[Formula: see text]; -actin-MS2[Formula: see text]) 的小鼠。使用内源标记的肌动蛋白转录本，我们报告 IGF2BP1[Formula: see text] 神经元具有更高的转录率和总肌动蛋白蛋白含量。此外，我们发现敲除神经元中的运输和锚定减少。总体而言，我们提出了一个理解 RBP 调控靶标 mRNA 的重要模型。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5631/9477413/c156f68349a3/pnas.2208465119fig05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5631/9477413/37e5066ead19/pnas.2208465119fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5631/9477413/0b45de89a3df/pnas.2208465119fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5631/9477413/8b52b9b0cb60/pnas.2208465119fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5631/9477413/136c16e4f29a/pnas.2208465119fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5631/9477413/c156f68349a3/pnas.2208465119fig05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5631/9477413/37e5066ead19/pnas.2208465119fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5631/9477413/0b45de89a3df/pnas.2208465119fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5631/9477413/8b52b9b0cb60/pnas.2208465119fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5631/9477413/136c16e4f29a/pnas.2208465119fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5631/9477413/c156f68349a3/pnas.2208465119fig05.jpg

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