These Mice Are About to Go Viral Because of the Nobel Prize!

The 2024 Nobel Prize in Physiology or Medicine has been announced, and the winners are two American scientists, Victor Ambros and Gary Ruvkun, in recognition of their discovery of microRNA and its role in post-transcriptional gene regulation. This discovery is considered a major breakthrough following the central dogma of molecular biology. The Nobel Committee stated that their findings reveal a new dimension of gene regulation, highlighting the essential role of microRNA in living organisms, including humans.

Figure 1. Victor Ambros and Gary Ruvkun^[1]

What is microRNA?

MicroRNA (miRNA) is a class of non-coding RNA molecules, about 20-24 nucleotides long, that play a regulatory role primarily in post-transcriptional gene regulation. These miRNA genes are first transcribed in the cell nucleus into primary miRNA transcripts (pri-miRNA). Under the action of the enzyme Drosha, they are cleaved into precursor miRNA (pre-miRNA) with a hairpin structure. Pre-miRNA is then transported to the cytoplasm by Ran-GTP/Exportin 5, where another enzyme, Dicer, cleaves it into a double-stranded miRNA of about 20-24 nucleotides. This double-stranded miRNA is quickly loaded into the RNA-induced silencing complex (RISC), where one strand is degraded, and the mature single-stranded miRNA molecule pairs with the target gene's 3’-UTR region to degrade or inhibit its translation. ^[2]

Figure 2. Overview of MicroRNA biosynthesis and function

Functions of microRNA

miRNAs are involved in various physiological and pathological processes, including developmental regulation, antiviral defense, immune function, organ/system diseases, and tumors.

miRNA and the Nervous System

miRNAs play a role in maintaining normal nervous system functions and in the development of neurodegenerative diseases such as Parkinson’s Disease (PD) and Alzheimer’s Disease (AD). For example, abnormal expression of miR-133b may lead to PD, as it is crucial for the feedback loop with its target gene Pitx3, which maintains dopamine neurons in the brain. Similarly, in AD, decreased levels of miR-29a, miR-29b-1, and miR-9 in the brain lead to increased levels of their target gene BACE1, a key gene involved in producing β-amyloid peptides, increasing AD risk.

miRNA in Metabolic Functions

miRNA also plays a significant role in metabolism. Liver-specific miR-122 is involved in regulating cholesterol and lipid metabolism in the liver. Research suggests that miR-122 could be a potential target for treating high cholesterol, but more studies are needed to explore its therapeutic applications.

Figure 3. The role of miR-122 in hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. ^[3]

Applications of microRNA in Disease Treatment

The therapeutic potential of microRNA in disease treatment is broad, though no miRNA-based drugs have officially entered the market yet. Most are still in the preclinical development phase. Some studies have shown significant progress in diagnosis, treatment, and prognosis, particularly for cancer and cardiovascular diseases.

GenoBioTX’s MicroRNA-Related Animal Models

As a company specializing in model organisms, GenoBioTX has developed a series of microRNA-related genetically edited mice to provide powerful tools for microRNA research. If you need these models or customized services, feel free to contact us.

Table 1. A selection of microRNA mouse models from GenoBioTX

Case Study in Research Achievements

The Cardiovascular Disease Laboratory at the Pediatric Research Institute of Guangzhou Women and Children's Medical Center, led by Dr. Weihao Deng, published a paper in the journal Circulation on how circular RNA CircMAP3K5 acts as a microRNA-22-3p sponge to promote the resolution of intimal hyperplasia through TET2-mediated smooth muscle cell differentiation. GenoBioTX contributed by constructing miR-22 knockout mouse models for this study.

Figure 4. circMAP3K5 model for the regulation of smooth muscle cell (SMC) phenotype ^[4]

The study involved vascular-specific overexpression of CircMAP3K5 in mice. Using miR-22-KO and SMC-Tet2-KO mouse models, further experiments demonstrated that CircMAP3K5 significantly inhibits the formation of neointima, offering a new therapeutic approach for neointimal hyperplasia and providing a theoretical basis for subsequent clinical research.

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Reference:

[1] The Nobel Prize in Physiology or Medicine 2024. Retrieved Oct 07，2024, from https://www.nobelprize.org/prizes/medicine/

[2] Diener C, Keller A, Meese E. Emerging concepts of miRNA therapeutics: from cells to clinic. Trends Genet. 2022;38(6):613-626. doi:10.1016/j.tig.2022.02.006

[3] Song K, Han C, Dash S, Balart LA, Wu T. MiR-122 in hepatitis B virus and hepatitis C virus dual infection. World J Hepatol. 2015;7(3):498-506. doi:10.4254/wjh.v7.i3.498

[4] Zeng Z, Xia L, Fan S, et al. Circular RNA CircMAP3K5 Acts as a MicroRNA-22-3p Sponge to Promote Resolution of Intimal Hyperplasia Via TET2-Mediated Smooth Muscle Cell Differentiation. Circulation. 2021;143(4):354-371. doi:10.1161/CIRCULATIONAHA.120.049715