Lin28a-flox Mouse

Lin28a is an RNA-binding protein. Initially discovered in Caenorhabditis elegans, it regulates stem cell differentiation and proliferation. In mammals, it also plays roles in cell cycle, growth, tissue repair, and metabolism (notably glucose metabolism) through let-7-dependent (binding to let-7) or independent (binding directly to mature mRNA) pathways [1].

In cardiac repair, LIN28a reintroduction in post-natal mice decreased cardiomyocyte maturation-associated polyploidization, enhanced cell cycle activity, and improved cardiac function after injury. In the adult heart, its overexpression attenuated cardiomyocyte apoptosis and improved survival after myocardial infarction, while its small molecule inhibitor blunted these pro-reparative effects. LIN28a was found to reprogram cardiomyocyte metabolism by increasing glycolysis and ATP production, and its target long non-coding RNA-H19 was identified as crucial for the observed effects on cardiomyocyte metabolism and cell cycle activity [2].

In muscle, a rare subset of Lin28a + Pax7-skeletal muscle stem cells (MuSCs) can respond to injury in adults, replenishing the Pax7 + MuSC pool. Conditional ablation and induction of Lin28a + MuSCs in adult mice showed their necessity and sufficiency for efficient muscle regeneration [3].

In renal fibrosis, in a mouse model of unilateral ureteral obstruction, overexpression of Lin28a inhibited the expression of renal fibrotic markers and Lin28a inhibited TGF-β-stimulated SMAD3 activity, suggesting it attenuates renal fibrosis [4].

In epilepsy, blocking LIN28A upregulation in all neuronal lineages after acute seizure in Nestin-Cre:Lin28aloxP/loxP (conditional KO [cKO]) mice alleviated adult-generated neuron-and hippocampus-associated cognitive impairments, and reduced the number of hilar PROX1-expressing ectopic granule cells [5].

In conclusion, Lin28a is crucial for various biological processes including stem cell-related functions, cardiac repair, muscle regeneration, and renal protection. Gene knockout and conditional knockout mouse models have been instrumental in revealing its role in disease conditions such as cardiac injury, muscle regeneration impairment, renal fibrosis, and epilepsy-related cognitive dysfunction, providing potential therapeutic targets for these diseases.