C-Terminal Extended Domain-Independent Telomere Maintenance: Modeling the Function of TIN2 Isoforms in Mus musculus

TIN2 (TERF1 interacting nuclear factor 2) is a telomeric shelterin complex component, essential for telomere protection and early embryonic development in mammals. In humans, TIN2 isoforms arise from alternative splicing, but their specific roles in vivo remain unclear. Here, we explore TIN2 isoform functions in the laboratory mouse Mus musculus. Our comparative analysis of TIN2 protein sequences reveals that mouse TIN2 (TINF2) closely resembles the human TIN2L isoform, both of which harbor a C-terminal extended domain (CTED) absent from the human TIN2 small (TIN2S) isoform. To further characterize the functions of TIN2 isoforms, we generated a Tinf2 LD (long-form deficiency) allele in M. musculus encoding a short form of TINF2 lacking the CTED. Mice heterozygous or homozygous for this Tinf2 LD allele were viable, fertile, and showed no tissue abnormalities. Furthermore, protein product of Tinf2 LD allele localized to telomeres and maintained telomere integrity in mouse embryonic fibroblasts, demonstrating that the CTED is dispensable for telomere protection and normal development in mice. These findings indicate functional redundancy among TIN2 isoforms and underscore the utility of the Tinf2 LD model for uncovering isoform-specific mechanisms of telomere regulation.