Involvement of LIN28A in Wnt-dependent regulation of hippocampal neurogenesis in the aging brain.

Hippocampal neurogenesis declines with aging. Wnt ligands and antagonists within the hippocampal neurogenic niche regulate the proliferation of neural progenitor cells and the development of new neurons, and the changes of their levels in the niche mediate aging-associated decline of neurogenesis. We found that RNA-binding protein LIN28A remained existent in neural progenitor cells and granule neurons in the adult hippocampus and that it decreased with aging. Lin28a knockout inhibited the responsiveness of neural progenitor cells to niche Wnt agonists and reduced neurogenesis, thus impairing pattern separation. Overexpression of Lin28a increased the proliferation of neural progenitor cells, promoted the functional integration of newborn neurons, restored neurogenesis in Wnt-deficient dentate gyrus, and rescued the impaired pattern separation in aging mice. Our data suggest that LIN28A regulates adult hippocampal neurogenesis as an intracellular mechanism by responding to niche Wnt signals, and its decrease is involved in aging-associated decline of hippocampal neurogenesis and related cognitive functions.