Choroid plexus‐derived miR‐204 regulates the number of quiescent neural stem cells in the adult brain

Abstract

Regulation of adult neural stem cell (NSC) number is critical for lifelong neurogenesis. Here, we identified a post-transcriptional control mechanism, centered around the microRNA 204 (miR-204), to control the maintenance of quiescent (q)NSCs. miR-204 regulates a spectrum of transcripts involved in cell cycle regulation, neuronal migration, and differentiation in qNSCs. Importantly, inhibition of miR-204 function reduced the number of qNSCs in the subependymal zone (SEZ) by inducing pre-mature activation and differentiation of NSCs without changing their neurogenic potential. Strikingly, we identified the choroid plexus of the mouse lateral ventricle as the major source of miR-204 that is released into the cerebrospinal fluid to control number of NSCs within the SEZ. Taken together, our results describe a novel mechanism to maintain adult somatic stem cells by a niche-specific miRNA repressing activation and differentiation of stem cells.

Sleep or deplete: how the choroid plexus helps to keep neural stem cells in balance

“…Thus, once activated the decision to self‐renew or to differentiate is of central importance for the stem cell. Lepko et al () now show that miR‐204 controls neurogenic priming and it will be worthwhile to investigate whether similar mechanisms also exist for gliogenic priming. Furthermore, new genetic tools will be required that allow for the analyses if the previous cell division history influences the activation and differentiation of NSCs.…”

“…Lepko et al () now show that quiescent, label‐retaining NSCs in the V‐SVZ are primed for neurogenesis and express mRNAs coding for stem cell activation and neuronal fate determination such as MEIS2 and SOX11. However, these genes are not translated in quiescent NSCs and they identify a post‐transcriptional control mechanism, in which microRNA 204 (miR‐204) derived from the ChP hinders translation of stem cell activators and fate determinants and therefore prevents their activation and subsequent differentiation.…”

“…Strikingly, inhibition of miR‐204 function using several complementary approaches increased the number of MEIS2‐expressing and thus activated LRCs, which was associated with an increase in newborn neurons expressing the microtubule‐associated protein doublecortin (DCX). Thus, miR‐204 secreted from the ChP limits the activation of quiescent NSCs, prevents their depletion and keeps them in a primed state (Lepko et al , ). What is the relevance of these novel findings and how do they add to preexisting knowledge regarding lifelong regulation of NSCs in the adult brain?…”

“…However, the mechanisms that keep them in a quiescent state remain poorly understood. The study from Lepko et al () gives new insights into how the quiescent state of NSCs is actively maintained, and it will be interesting to test whether miR‐204 regulates the activation of regionally distinct NSC populations to an equal degree. The majority of V‐SVZ NSCs do not re‐enter long‐term quiescence upon activation (Calzolari et al , ; Obernier et al , ), similar to hippocampal NSCs where intravital imaging showed that most NSCs do not return to long‐term quiescence upon initial activation (Pilz et al , ).…”

Aggregated spatio-temporal division patterns emerge from reoccurring divisions of neural stem cells

“…In the adult mouse forebrain, neuronal activity in mossy cells or in granule cells regulates the activation of radial neural stem cells of the dentate gyrus (Dong et al, 2019;Yeh et al, 2018) . In the subventricular zone, neural stem cell (NSC) cycling is inhibited by direct contacts with endothelial cells (Ottone et al, 2014) , or by the release of miR204 from the choroid plexus (Lepko et al, 2019) . In mouse and zebrafish adult neurogenic zones, Notch activity maintains NSCs in quiescence (Alunni et al, 2013;Chapouton et al, 2010;Ehm et al, 2010) , in particular in the immediate neighborhood of dividing cells (Chapouton et al, 2010) .…”