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 [3]. It plays a role in regulating gene expression by influencing the splicing of U12-type genes. It is associated with processes like ciliogenesis and WNT signaling, and is conserved across species from zebrafish to human [1,3]. Genetic models, such as knockdown in zebrafish embryos and human cell lines, are valuable for studying its function.

In human cell lines, partial reduction of ZCRB1 expression via CRISPR-Cas9 and siRNA leads to dysregulation of U12-type gene splicing and expression, mainly due to U12 mono-snRNA dysregulation. This results in down-regulation of ciliogenesis-related genes and up-regulation of WNT signaling [1]. In zebrafish embryos, zcrb1 CRISPR-Cas12a knockdown causes gross developmental and body axis abnormalities, disrupted ciliogenesis, and up-regulated WNT signaling, complementing the human cell studies [1]. In glioblastoma multiforme (GBM), overexpression of ZCRB1 promotes the formation of circHEATR5B, which encodes a protein that suppresses aerobic glycolysis and proliferation in GBM cells [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 in DNA damage response [4].

In summary, Zcrb1 is crucial for normal cellular and developmental processes, mainly through its role in minor spliceosome-mediated gene splicing. Its dysregulation is associated with various diseases, including GBM and HNSCC. The use of gene-knockdown models in zebrafish and human cell lines has been instrumental in uncovering these associations, providing insights into potential disease mechanisms and therapeutic targets.

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/