在遗传性THOC6智力障碍综合征中,mRNA处理缺陷的机制
Elizabeth Werren1, Geneva LaForce2, Anshika Srivastava3
1University of Michigan-Ann Arbor.
Research square
|September 18, 2023
概括
基因THOC6导致THOC6智力障碍综合征 (TIDS). 失去THOC6功能导致mRNA错误拼接并影响神经发育,为TIDS神经病理学提供了新的见解.
科学领域:
- 遗传学 是一个遗传学.
- 分子生物学分子生物学
- 神经科学是一个神经科学.
背景情况:
- THOC6是自体逆性THOC6智力障碍综合征 (TIDS) 的遗传原因.
- THOC6对于形成转录出口 (TREX) 四分体是必不可少的,与酵母TREX二分体不同.
- 哺乳动物mRNA处理涉及TREX四聚合物的独特功能.
研究的目的:
- 使用人类和小鼠TIDS模型研究新的THOC6依赖的TREX四聚合物功能.
- 阐明THOC6在mRNA处理中的作用及其对TIDS神经病理学的影响.
主要方法:
- 利用THOC6智力障碍综合征 (TIDS) 的人类和小鼠模型.
- 在THOC6功能丧失 (LOF) 细胞中分析了TREX成员的表达,定位和结合亲和力 (ALYREF).
- 在神经组织中检查了mRNA处理和拼接.
主要成果:
- 双性THOC6 LOF变体没有改变TREX成员的表达或定位,但降低了ALYREF结合亲和力.
- 在THOC6 LOF细胞中没有观察到TREX核出口功能受损.
- 在人类和小鼠神经组织中观察到mRNA错误拼接,表明THOC6在mRNA处理中的新角色.
- 证明了THOC6对调节人类皮质形成中的信号通路的要求,影响了从增殖到神经发生的过渡.
结论:
- 在哺乳动物的mRNA处理中,THOC6起着至关重要的作用,与酵母TREX二元函数不同.
- THOC6缺乏导致mRNA错误拼接并影响皮质形成,为TIDS神经病理学提供了洞察力.
- 这项研究揭示了新的THOC6依赖机制,协调mRNA处理和神经发育.
更多相关视频
08:22A Novel Strategy Combining Array-CGH, Whole-exome Sequencing and In Utero Electroporation in Rodents to Identify Causative Genes for Brain Malformations
Published on: December 1, 2017
8.7K
07:14Optogenetic Phase Transition of TDP-43 in Spinal Motor Neurons of Zebrafish Larvae
Published on: February 25, 2022
6.0K
相关概念视频
01:31Translation
14.9K
Translation is the process of synthesizing proteins from the genetic information carried by messenger RNA (mRNA). Following transcription, it constitutes the final step in the expression of genes. This process is carried out by ribosomes, complexes of protein and specialized RNA molecules. Ribosomes, transfer RNA (tRNA), and other proteins produce a chain of amino acids—the polypeptide—as the end product of translation.
Translation Produces the Building Blocks of Life
Proteins are...
Translation Produces the Building Blocks of Life
Proteins are...
14.9K
02:18Alternative RNA Splicing
21.3K
Alternative RNA splicing is the regulated splicing of exons and introns to produce different mature mRNAs from a single pre-mRNA. Unlike in constitutive splicing where a single gene produces a single type of mRNA, alternative splicing allows an organism to produce multiple proteins from a single gene and plays an important role in protein diversity.
There are five types of alternative RNA splicing that vary in the ways the pre-mRNA segments are removed or retained in the mature mRNA. The first...
There are five types of alternative RNA splicing that vary in the ways the pre-mRNA segments are removed or retained in the mature mRNA. The first...
21.3K
02:31Nuclear Export of mRNA
7.7K
Before mRNAs are exported to the cytoplasm, it is crucial to check each mRNA for structural and functional integrity. Eukaryotic cells use several different mechanisms, collectively known as mRNA surveillance, to look for irregularities in mRNAs. Irregular or aberrant mRNA are rapidly degraded by various enzymes. If a defective mRNA escapes the surveillance, it would be translated into a protein which would either be non-functional or not function properly. One of the primary irregularities in...
7.7K
02:27Nonsense-mediated mRNA Decay
10.7K
The Upf proteins that carry out nonsense-mediated decay (NMD) are found in all eukaryotic organisms, including humans. Each protein has an individual role, but they need to work in collaboration. Upf1 is an ATP-dependent RNA helicase that unwinds the RNA helix. Because Upf1 can unwind any RNA, Upf2 and Upf3 are required to help Upf1 discriminate between nonsense and normal mRNAs.
Usually, Upf3 binds to an Exon Junction Complex (EJC) at mRNA splice sites. If a ribosome fully translates the mRNA,...
Usually, Upf3 binds to an Exon Junction Complex (EJC) at mRNA splice sites. If a ribosome fully translates the mRNA,...
10.7K
01:56Riboswitches
8.2K
Riboswitches are non-coding mRNA domains that regulate the transcription and translation of downstream genes without the help of proteins. Riboswitches bind directly to a metabolite and can form unique stem-loop or hairpin structures in response to the amount of the metabolite present. They have two distinct regions – a metabolite-binding aptamer and an expression platform.
The aptamer has high specificity for a particular metabolite which allows riboswitches to specifically regulate...
The aptamer has high specificity for a particular metabolite which allows riboswitches to specifically regulate...
8.2K
02:51mRNA Stability and Gene Expression
5.6K
The structure and stability of mRNA molecules regulates gene expression, as mRNAs are a key step in the pathway from gene to protein. In eukaryotes, the half-life of mRNA varies from a few minutes up to several days. mRNA stability is essential in growth and development. The absence of the proteins regulating its stability, such as tristetraprolin in mice, can cause systemic issues, including bone marrow overgrowth, inflammation, and autoimmunity.
Cis-acting Elements involved in mRNA stability
Cis-acting Elements involved in mRNA stability
5.6K