Dis3l2-flox Mouse

DIS3L2 is an RNA-binding protein with 3'-5' exoribonuclease activity. It contains RNA-binding domains (two CSD domains and one S1 domain) and an RNB domain for exoribonuclease activity. DIS3L2 is predominantly in the cytoplasm, where it recognizes and degrades uridylated cytoplasmic RNAs like pre-microRNA, mature microRNA, mRNA, and non-coding RNAs, playing a key role in cytoplasmic RNA surveillance and decay. It is involved in multiple biological processes such as cell division, proliferation, differentiation, and apoptosis [1]. Mutations in DIS3L2 have been linked to Perlman syndrome [1,7].

Conditional ablation of Dis3l2 in pre-meiotic germ cells of male mice using Stra8-Cre mice leads to impaired spermatogonial differentiation, hindered spermatocyte meiotic progression, and cell apoptosis, resulting in defective spermatogenesis and male infertility. This indicates the crucial role of DIS3L2-mediated RNA degradation in maintaining the correct transcriptome during spermatogenesis [2].

In female mice, oocyte-specific Dis3l2 knockout (Dis3l2cKO) causes almost all oocytes to arrest at the germinal vesicle stage, and female mice are infertile, as uridylated-poly(A) RNAs accumulate due to insufficient degradation by DIS3L2 [3].

In Drosophila, a dis3L2 null mutant shows that the catalytic activity of Dis3L2 is required to control cell proliferation, and in human kidney HEK-293T cells, loss of DIS3L2 also results in cell proliferation, with an increase in the PI3-Kinase/AKT signalling pathway [4].

In colorectal cancer cells, knockdown of DIS3L2 reduces the viability of highly oncogenic cells and disturbs metastasis-associated properties, and downregulates the mTOR signalling pathway [5].

In hepatocellular carcinoma, DIS3L2 promotes cancer progression via hnRNP U-mediated alternative splicing, generating an oncogenic splicing variant, Rac1b [6].

In conclusion, DIS3L2 is essential for cytoplasmic RNA surveillance and decay, and is involved in various biological processes. Through gene knockout and conditional knockout mouse models, as well as other model-based research, its roles in spermatogenesis, oocyte maturation, cell proliferation, and cancer development have been revealed. The study of DIS3L2 provides insights into RNA metabolism and the mechanisms underlying diseases such as Perlman syndrome and various cancers.