Zcrb1-KO Mouse

Zcrb1, also known as zinc finger CCHC-type and RNA-binding motif 1 (alias MADP-1), is a core component of the U12 mono-snRNP minor spliceosome. It plays a crucial role in the splicing of U12-type genes, influencing gene expression across multiple cellular processes. The gene is involved in pathways such as ciliogenesis and WNT signaling, and is conserved across species from zebrafish to humans [1,3].

In human cell lines, partial reduction of Zcrb1 expression using CRISPR-Cas9 and siRNA leads to dysregulation of U12-type gene splicing and expression, mainly due to U12 mono-snRNA dysregulation. RNA-Seq analysis shows down-regulation of ciliogenesis-related genes and up-regulation of WNT signaling. In zebrafish embryos, zcrb1 CRISPR-Cas12a knockdown causes developmental and body axis abnormalities, disrupted ciliogenesis, and up-regulated WNT signaling, highlighting its conserved role in cellular and developmental processes [1]. In glioblastoma multiforme (GBM), ZCRB1 is expressed at low levels. Overexpression of ZCRB1 suppresses aerobic glycolysis and proliferation in GBM cells by promoting the formation of circHEATR5B, which encodes a protein that interacts with JMJD5, phosphorylates it, and reduces its stability [2]. In head and neck squamous cell carcinoma (HNSCC), knockdown of ZCRB1 impairs cell survival, while overexpression promotes tumor cellular proliferation, and its depletion contributes to aberrant splicing events involving DNA damage response [4]. In hepatocellular carcinoma (HCC), knockdown of ZCRB1 impairs the proliferation, invasion, migration, and colony formation in HCC cell lines [5].

In summary, Zcrb1 is essential for normal cellular and developmental processes through its role in minor spliceosome-mediated gene splicing. Model-based research, such as gene knockdown in human cell lines and zebrafish embryos, has revealed its significance in ciliogenesis, WNT signaling, and in various cancer types including GBM, HNSCC, and HCC, providing potential therapeutic targets for these diseases.

References:

1. Powell-Rodgers, Geralle, Pirzada, Mujeeb Ur Rehman, Richee, Jahmiera, Stratman, Amber N, Djuranovic, Sergej. 2024. Role of U11/U12 minor spliceosome gene ZCRB1 in Ciliogenesis and WNT Signaling. In bioRxiv : the preprint server for biology, , . doi:10.1101/2024.08.09.607392. https://pubmed.ncbi.nlm.nih.gov/39149385/

2. Song, Jian, Zheng, Jian, Liu, Xiaobai, Zhang, Mengyang, Liu, Yunhui. 2022. A novel protein encoded by ZCRB1-induced circHEATR5B suppresses aerobic glycolysis of GBM through phosphorylation of JMJD5. In Journal of experimental & clinical cancer research : CR, 41, 171. doi:10.1186/s13046-022-02374-6. https://pubmed.ncbi.nlm.nih.gov/35538499/

3. Wang, Haoran, Gao, Mary X, Li, Linda, Hori, Naohiro, Sato, Kenzo. 2006. Isolation, expression, and characterization of the human ZCRB1 gene mapped to 12q12. In Genomics, 89, 59-69. doi:. https://pubmed.ncbi.nlm.nih.gov/16959469/

4. Chen, Chaoqun, Huang, Fang, Li, Xiaojie, Qi, Yangfan, Wang, Yang. 2024. Identification of splicing factors signature predicting prognosis risk and the mechanistic roles of novel oncogenes in HNSCC. In Biochimica et biophysica acta. Molecular basis of disease, 1870, 167115. doi:10.1016/j.bbadis.2024.167115. https://pubmed.ncbi.nlm.nih.gov/38458543/

5. Ma, Yun-Long, Yang, Ya-Fei, Wang, Han-Chao, Wang, Dong-Xu, Li, Tao. 2023. A novel prognostic scoring model based on copper homeostasis and cuproptosis which indicates changes in tumor microenvironment and affects treatment response. In Frontiers in pharmacology, 14, 1101749. doi:10.3389/fphar.2023.1101749. https://pubmed.ncbi.nlm.nih.gov/36909185/