GSE182848
The piRNA pathway sustains adult neurogenesis by reducing protein synthesis and cellular senescence
Neural progenitor cells (aNPCs) ensure lifelong neurogenesis in the mammalian hippocampus. Proper regulation of aNPC fate entails important implications for brain plasticity and healthy aging. Piwi proteins and the small noncoding RNAs interacting with them (piRNAs) are best known in gonads as repressors of transposons. Here, we show that Piwil2 (Mili) and piRNAs are abundant in aNPCs of the postnatal mouse hippocampus and demonstrate that this pathway is essential for proper neurogenesis. Particularly, depleting the piRNA pathway in aNPCs impaired neurogenesis while increasing senescence and the generation of reactive glia. Moreover, depletion of the piRNA pathway primarily elevated 5S ribosomal RNA, SINEB1 and mRNAs encoding ribosomal proteins and regulators of translation, resulting in higher polysome density and protein synthesis upon differentiation. Our results provide evidence of an essential role for the piRNA pathway in maintaining homeostasis to sustain neural stem cell fate, underpinning its possible involvement in brain plasticity and successful aging. Overall design: mRNA sequencing was performed on proliferative (DIF0), or differentiating (DIF4, DIF7 or DIF14) primary neural stem cells from the adult hippocampus of C57BL/6 mice. Separate aNSC cultures were stably transfected with a short-hairpin scramble RNA bearing lentiviral vector, or a anti-Mili short-hairpin RNA to stably knock-down the level of MILI protein. Three samples from each differentiating timepoint (n = 4), and each transfection (n = 3), were used for mRNA sequencing in duplicate for a total of 72 quantitative samples.