The telomeric protein AKTIP/Ft1 intercepts lamin metabolism and is important in mouse development

Aging is defined as the time-dependent functional decline that affects most living organisms. Impairments of telomeres maintenance, defects in DNA structure and metabolism, loss of nuclear structure integrity may accelerate events that will lead to premature aging []. We have recently identified a novel telomeric protein named AKTIP/Ft1. It interacts with telomeric DNA and with both TRF1 and TRF2. Its depletion causes in vitro multiple telomeric signals, which are hallmarks of telomere replication defects [Burla et al., Plos genetics, 2015]. AKTIP is manly localized at the nuclear rim []. According to its localization we found that it interacts with component of the nuclear lamina, such as Lamin A/C and Lamin B1. In cell that express mutated version of Lamin A its binding with telomeric DNA is impaired, its cellular signal is mislocalized and reduced. AKTIP depleted cells show premature aging traits such as loss of chromatin organization. These data suggest an interplay between AKTIP and lamins [Burla et al., submitted]. Indeed AKTIP in vitro is involved in mechanisms which perturbation lead to aging. Given the important role of AKTIP in vitro we wanted to investigated on the role of AKTIP (Ft1) in vivo, through the production and characterization of a knockout-first (KOF) mouse model, in which the transgenic cassette inhibits AKTIP (Ft1) expression, indeed KOF/KOF animals systematically exhibiting substantial reduction of mRNA (≤30% of WT). The analysis of these mice showed that AKTIP (Ft1) is critically important particularly during the early phases of mouse development. Indeed, 20.5% of homozygous KOF mice die at postnatal day 12-13, display gross defects in the skeleton and in the skin, in addition to a strong reduction in body weight. The rest 79.5% of KOF/KOF animals show reduced survival respect of their wild type counterparts. They show growth defect exacerbated during mice lifespan. Intriguingly, male KOF/KOF mice are sterile. We reported a tissue specific phenotype for AKTIP (Ft1) depleted mice, affecting organs with high proliferative rate such as testicles, skin and bone. Our hypothesis is that AKTIP depletion affects the proliferative status of progenitor cells leading to the exhaustion of stem cell compartment and arising a premature aging phenotype.