Molecular profiling of aged neural progenitors identifies Dbx2 as a candidate regulator of age‐associated neurogenic decline

Abstract

SummaryAdult neurogenesis declines with aging due to the depletion and functional impairment of neural stem/progenitor cells (NSPCs). An improved understanding of the underlying mechanisms that drive age‐associated neurogenic deficiency could lead to the development of strategies to alleviate cognitive impairment and facilitate neuroregeneration. An essential step towards this aim is to investigate the molecular changes that occur in NSPC aging on a genomewide scale. In this study, we compare the transcriptional, histone methylation and DNA methylation signatures of NSPCs derived from the subventricular zone (SVZ) of young adult (3 months old) and aged (18 months old) mice. Surprisingly, the transcriptional and epigenomic profiles of SVZ‐derived NSPCs are largely unchanged in aged cells. Despite the global similarities, we detect robust age‐dependent changes at several hundred genes and regulatory elements, thereby identifying putative regulators of neurogenic decline. Within this list, the homeobox gene Dbx2 is upregulated in vitro and in vivo, and its promoter region has altered histone and DNA methylation levels, in aged NSPCs. Using functional in vitro assays, we show that elevated Dbx2 expression in young adult NSPCs promotes age‐related phenotypes, including the reduced proliferation of NSPC cultures and the altered transcript levels of age‐associated regulators of NSPC proliferation and differentiation. Depleting Dbx2 in aged NSPCs caused the reverse gene expression changes. Taken together, these results provide new insights into the molecular programmes that are affected during mouse NSPC aging, and uncover a new functional role for Dbx2 in promoting age‐related neurogenic decline.

X-ray irradiated cultures of mouse cortical neural stem/progenitor cells recover cell viability and proliferation with dose-dependent kinetics

“…1a,b, sham treatments resulted in low levels of cell death throughout the time course (roughly 10% at 24 h and 8d). This is in line with the background cell death in NSPC in vitro cultures detected in other studies 29 , which is at least partially due to the enzymatic treatment needed to detach the cells before trypan blue analysis. The slightly higher fraction (roughly 15%) of trypan blue-positive cells observed in sham samples at 4 h post-irradiation may reflect a mild stress caused by keeping the cultures at room temperature and atmospheric CO 2 during irradiation.…”

Extensive transcriptional and chromatin changes underlie astrocyte maturationin vivoand in culture

“…Astrocyte maturation, the last stage of astrocyte differentiation, takes place from early postnatal to young adult stages, when proliferating immature astrocytes cease to divide and aquire the full spectrum of astrocyte functions observed in the adult brain (Molofsky and Deneen, 2015;Yang et al, 2013). In this study, we have analysed in detail the transcriptional and chromatin changes that occur during maturation of astrocytes in the mouse forebrain.…”

“…Interestingly, their roles in neurons seem to be mediated at least partially by cross-repression of alternative neuronal subtype programmes, suggesting that their expression in astrocytes might contribute to the global suppression of neuronal programmes. Moreover Dbx2 and Fezf2 have also been shown to promote NSC quiescence (Berberoglu et al, 2014;Lupo et al, 2018), thus these two factors might contribute to suppressing the proliferative capacity of mature astrocytes. In addition to such repressive activities, each of the four factors also induced maturity-associated genes in cultured astrocytes, suggesting that they may also have transactivating functions in the astrocytic context.…”

“…First, a "gliogenic switch" enables NSCs to progress from neurogenesis to the generation of astrocytes and oligodendrocytes. Specified glial precursors then migrate from the progenitor zones to the brain parenchyma where they proliferate and differentiate during early postnatal stages (Ge et al, 2012;Molofsky and Deneen, 2015). During a subsequent phase of maturation in the first few postnatal weeks, immature astrocytes exit the cell cycle and aquire a fully mature phenotype (Molofsky and Deneen, 2015).…”

Granulins Regulate Aging Kinetics in the Adult Zebrafish Telencephalon

“…a primary reason for this impaired tissue homeostasis and regeneration is age-related exhaustion of tissue-specific stem cells, a process observed in various organs [3][4][5], including the mammalian brain [6][7][8][9][10]. Although prominent age-associated changes, including decreased neurogenesis and changes in the lateral ventricle choroid plexus [11][12][13], have Cells 2020, 9, 2 of 25 been detected in the aging mammalian brain, comparisons of neural stem cell transcriptomes have revealed a remarkably small set of differentially regulated transcripts, which are largely associated with cell cycle regulation, neuronal differentiation, and inflammation [10,[14][15][16]. These analyses support the hypothesis that specific changes in a limited number of key regulators influenced by both intrinsic [16] and extrinsic [11,12,17,18] aging-associated pathways lead to the aging of the neural stem cell compartment.…”