A Transcriptional Mechanism Integrating Inputs from Extracellular Signals to Activate Hippocampal Stem Cells

Abstract

SummaryThe activity of adult stem cells is regulated by signals emanating from the surrounding tissue. Many niche signals have been identified, but it is unclear how they influence the choice of stem cells to remain quiescent or divide. Here we show that when stem cells of the adult hippocampus receive activating signals, they first induce the expression of the transcription factor Ascl1 and only subsequently exit quiescence. Moreover, lowering Ascl1 expression reduces the proliferation rate of hippocampal stem cells, and inactivating Ascl1 blocks quiescence exit completely, rendering them unresponsive to activating stimuli. Ascl1 promotes the proliferation of hippocampal stem cells by directly regulating the expression of cell-cycle regulatory genes. Ascl1 is similarly required for stem cell activation in the adult subventricular zone. Our results support a model whereby Ascl1 integrates inputs from both stimulatory and inhibitory signals and converts them into a transcriptional program activating adult neural stem cells.

Transcription factors COUP-TFI and COUP-TFII are required for the production of granule cells in the mouse olfactory bulb

“…In particular, Ascl1 plays a crucial role in activating neural stem/ progenitor cells in the adult SVZ (Andersen et al, 2014). Analyzing the expression of Ascl1 at P10 and P21 showed a significant increase in the number of Ki67+/Ascl1+ proliferating neural stem/ progenitor cells in the caudal SVZ of COUP-TF double conditional mutant mice compared with control mice (8.7-fold increase at P10 and 10.8-fold increase at P21, Fig.…”

“…1J,K). A subset of NSCs and rapidly dividing intermediate progenitor cells have been shown to express the proneural basic helix-loop-helix transcription factor achaete-scute homolog 1 (Ascl1, also known as Mash1) (Parras et al, 2004;Kohwi et al, 2005;Kim et al, 2011;Andersen et al, 2014;Mich et al, 2014). By immunostaining for COUP-TFI and Ascl1, we found that many COUP-TFI+ cells in the adult SVZ expressed Ascl1 (Fig.…”

“…The proneural gene Ascl1 has been shown to promote neural stem/progenitor cell proliferation and neurogenesis in the embryonic and adult brain (Bertrand et al, 2002;Andersen et al, 2014;Imayoshi and Kageyama, 2014). In particular, Ascl1 plays a crucial role in activating neural stem/ progenitor cells in the adult SVZ (Andersen et al, 2014).…”

How can we exploit the brain’s ability to repair itself?

“…In other words, without the existence of neural stem cells, self-repair would not be possible. In this direction, recent evidence supporting the key role of Ascl1 in determining the re-activation of Neural Stem Cells offers a promising approach to overcome cell dormancy [19]. The examination of the environmental cues and conditions promoting an increase in neurogenic activity will be fundamental to re-activate the latent neurogenic potential of the adult human brain therapeutically.…”

Genetic mechanisms regulating proliferation and cell specification in the Drosophila embryonic CNS

“…Further, Oct1-2 in mammalians is related to Pdm1-2 in Drosophila [293]. In addition, Ascl1 i.e., the mammalian ortholog of Ase, induces daughter proliferation in the mouse adult brain [294,295].…”