Age-related neurogenesis decline in the subventricular zone is associated with specific cell cycle regulation changes in activated neural stem cells.

Mathieu Daynac,Lise Morizur,Marc-André Mouthon,François D Boussin,Alexandra Chicheportiche

doi:10.1038/srep21505

Abstract

Although neural stem cells (NSCs) sustain continuous neurogenesis throughout the adult lifespan of mammals, they progressively exhibit proliferation defects that contribute to a sharp reduction in subventricular neurogenesis during aging. However, little is known regarding the early age-related events in neurogenic niches. Using a fluorescence-activated cell sorting technique that allows for the prospective purification of the main neurogenic populations from the subventricular zone (SVZ), we demonstrated an early decline in adult neurogenesis with a dramatic loss of progenitor cells in 4 month-old young adult mice. Whereas the activated and quiescent NSC pools remained stable up to 12 months, the proliferative status of activated NSCs was already altered by 6 months, with an overall extension of the cell cycle resulting from a specific lengthening of G1. Whole genome analysis of activated NSCs from 2- and 6-month-old mice further revealed distinct transcriptomic and molecular signatures, as well as a modulation of the TGFβ signalling pathway. Our microarray study constitutes a cogent identification of new molecular players and signalling pathways regulating adult neurogenesis and its early modifications.

Highlights

Months, associated with a decrease by half of the number of colonies produced by subventricular zone (SVZ) progenitors in vitro[13,15]
It is well known that SVZ neurogenesis decreases in the aging adult mouse brain[13,16,18,23], its early decline with age and the underlying molecular mechanisms have not been elucidated to date
To accurately determine the progression of SVZ neurogenesis with age, we quantified NSCs and their progeny by fluorescent-activated cell sorting (FACS) at 2, 4, 6, 9 and 12 months based on the detection of 3 different cell surface markers, LeX, CD24 and EGFR, as previously reported[5,18,29]. These markers allow for the identification of the following 5 neurogenic cell populations (Fig. 1A; for clarity, the negative markers are not indicated): (i) LeXbright cells, i.e., quiescent neural stem cells (qNSCs); (ii) LeX+ EGFR+ cells, i.e., Activated NSCs (aNSCs); (iii) EGFR+ cells, i.e., transit amplifying cells (TACs); (iv) EGFR+ CD24+, i.e., Im

Summary

Introduction

Months, associated with a decrease by half of the number of colonies (neurospheres) produced by SVZ progenitors in vitro[13,15]. The cell surface carbohydrate Lewis-X (LeX) has been shown as a potent and reliable marker to label and sort NSCs in the adult SVZ5,27–29. We used our previously published FACS technique[5,29] to follow different cell populations in the SVZ in 2- to 12-month old mice. We observed that the NSC pool stayed constant, there was an early decrease in the number of progenitor cells and neuroblasts in young adult mice. We demonstrated a specific decrease in aNSC proliferation with a lengthening of their G1 phase of the cell cycle as early as 6 months. A microarray analysis using whole-genome arrays showed, for the first time, a clear cellular evolution in aNSCs from 2- and 6-month-old mice with distinct transcriptional profiles

Methods

Results

Conclusion