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脑内 tRNA 的细胞类型特异性表达调节细胞内稳态。

Cell-type-specific expression of tRNAs in the brain regulates cellular homeostasis.

机构信息

Department of Cellular and Molecular Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA; The Howard Hughes Medical Institute.

Department of Medicine, Division of Endocrinology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Bioengineering, Bioinformatics & Systems Biology Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.

出版信息

Neuron. 2024 May 1;112(9):1397-1415.e6. doi: 10.1016/j.neuron.2024.01.028. Epub 2024 Feb 19.

DOI:10.1016/j.neuron.2024.01.028
PMID:38377989
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11065635/
Abstract

Defects in tRNA biogenesis are associated with multiple neurological disorders, yet our understanding of these diseases has been hampered by an inability to determine tRNA expression in individual cell types within a complex tissue. Here, we developed a mouse model in which RNA polymerase III is conditionally epitope tagged in a Cre-dependent manner, allowing us to accurately profile tRNA expression in any cell type in vivo. We investigated tRNA expression in diverse nervous system cell types, revealing dramatic heterogeneity in the expression of tRNA genes between populations. We found that while maintenance of levels of tRNA isoacceptor families is critical for cellular homeostasis, neurons are differentially vulnerable to insults to distinct tRNA isoacceptor families. Cell-type-specific translatome analysis suggests that the balance between tRNA availability and codon demand may underlie such differential resilience. Our work provides a platform for investigating the complexities of mRNA translation and tRNA biology in the brain.

摘要

tRNA 生物发生缺陷与多种神经退行性疾病相关，但由于无法在复杂组织中的单个细胞类型中确定 tRNA 的表达，我们对这些疾病的理解受到了阻碍。在这里，我们开发了一种条件性地在 Cre 依赖性方式下标记 RNA 聚合酶 III 的小鼠模型，使我们能够在体内准确地描绘任何细胞类型中的 tRNA 表达情况。我们研究了不同神经细胞类型中的 tRNA 表达情况，揭示了 tRNA 基因在群体之间表达的巨大异质性。我们发现，虽然维持 tRNA 同工型家族的水平对于细胞内稳态至关重要，但神经元对不同 tRNA 同工型家族的损伤具有不同的易感性。细胞类型特异性翻译组分析表明，tRNA 可用性和密码子需求之间的平衡可能是这种差异恢复的基础。我们的工作为研究大脑中 mRNA 翻译和 tRNA 生物学的复杂性提供了一个平台。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2446/11065635/8bcb425dc207/nihms-1969755-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2446/11065635/c2a64d63397a/nihms-1969755-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2446/11065635/c6ffcb28eafc/nihms-1969755-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2446/11065635/cd66d177ce58/nihms-1969755-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2446/11065635/885cdf155e78/nihms-1969755-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2446/11065635/feb9bb3656b3/nihms-1969755-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2446/11065635/b2198eea4d4d/nihms-1969755-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2446/11065635/8bcb425dc207/nihms-1969755-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2446/11065635/c2a64d63397a/nihms-1969755-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2446/11065635/c6ffcb28eafc/nihms-1969755-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2446/11065635/cd66d177ce58/nihms-1969755-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2446/11065635/885cdf155e78/nihms-1969755-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2446/11065635/feb9bb3656b3/nihms-1969755-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2446/11065635/b2198eea4d4d/nihms-1969755-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2446/11065635/8bcb425dc207/nihms-1969755-f0008.jpg

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本文引用的文献

[1]
RREB1 regulates neuronal proteostasis and the microtubule network.

Sci Adv. 2024-1-12

[2]
tRNA Dysregulation in Neurodevelopmental and Neurodegenerative Diseases.

Annu Rev Cell Dev Biol. 2023-10-16

[3]
Chromatin remodeling by Pol II primes efficient Pol III transcription.

Nat Commun. 2023-6-16

[4]
Commissural dentate granule cell projections and their rapid formation in the adult brain.

PNAS Nexus. 2023-3-20

[5]
Pyramidal neurons form active, transient, multilayered circuits perturbed by autism-associated mutations at the inception of neocortex.

Cell. 2023-4-27

[6]
Two isoleucyl tRNAs that decode synonymous codons divergently regulate breast cancer metastatic growth by controlling translation of proliferation-regulating genes.

Nat Cancer. 2022-12

[7]
The tRNA regulome in neurodevelopmental and neuropsychiatric disease.

Mol Psychiatry. 2022-8

[8]
Hypothalamic miR-1983 Targets Insulin Receptor β and the Insulin-mediated miR-1983 Increase Is Blocked by Metformin.

Endocrinology. 2022-1-1

[9]
Cell type-specific analysis by single-cell profiling identifies a stable mammalian tRNA-mRNA interface and increased translation efficiency in neurons.

Genome Res. 2022-1

[10]
tRNAscan-SE 2.0: improved detection and functional classification of transfer RNA genes.

Nucleic Acids Res. 2021-9-20

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