Piwil2 (Mili) sustains neurogenesis and prevents cellular senescence in the postnatal hippocampus

Abstract

Adult neural progenitor cells (aNPCs) ensure lifelong neurogenesis in the mammalian hippocampus. Proper regulation of aNPC fate has thus important implications for brain plasticity and healthy aging. Piwi proteins and the small noncoding RNAs interacting with them (piRNAs) have been proposed to control memory and anxiety, but the mechanism remains elusive. Here, we show that Piwil2 (Mili) is essential for proper neurogenesis in the postnatal mouse hippocampus. RNA sequencing of aNPCs and their differentiated progeny reveal that Mili and piRNAs are dynamically expressed in neurogenesis. Depletion of Mili and piRNAs in the adult hippocampus impairs aNPC differentiation toward a neural fate, induces senescence, and generates reactive glia. Transcripts modulated upon Mili depletion bear sequences complementary or homologous to piRNAs and include repetitive elements and mRNAs encoding essential proteins for proper neurogenesis. Our results provide evidence of a critical role for Mili in maintaining fitness and proper fate of aNPCs, underpinning a possible involvement of the piRNA pathway in brain plasticity and successful aging.

piRNAs in the human retina and retinal pigment epithelium reveal a potential role in intracellular trafficking and oxidative stress

“…50 Recently, PIWIL proteins and piRNAs have been demonstrated to be involved in the neurogenesis via regulating proliferation, differentiation, survival, and cellular fate of adult neural progenitor cells in the postnatal hippocampus. 51 Additionally, piRNA's role in regulating neuronal differentiation via interacting with cold shock domain containing RNA binding proteins has been validated in human embryonal carcinoma cells. 52 Furthermore, the same group demonstrated that PIWIL4 modulated neuronal differentiation in NT2 cells.…”

Interplay between RNA interference and transposable elements in mammals

“…In addition to Dicer-driven RNAi, data implicate piwi-interacting RNAs (piRNAs), a class of small RNAs, in the control of TEs ( 54 , 55 ). The piRNA pathway is a well-documented anti-TE mechanism acting in the germline, through the generation of piRNAs transcribed from piRNA clusters ( 56 ).…”

Exploring the brain epitranscriptome: perspectives from the NSAS summit

“…Davide De Pietri Tonelli (Italian Institute of Technology-Genova, Italy) explored the involvement of small noncoding RNAs, such as the Piwi-interacting RNAs (piRNAs), in adult neurogenesis ( Gasperini et al, 2023 ). Depletion of Piwil2 and piRNAs through knockdown or the aging process results in an increased activation of the ROS pathway and inflammation in neural stem cells of the adult mouse hippocampus, ultimately leading to increased astrogenesis.…”