Id4 eliminates the pro-activation factor Ascl1 to maintain quiescence of adult hippocampal stem cells

Abstract

SUMMARY Quiescence is essential for the long-term maintenance of adult stem cells and tissue homeostasis. However, how stem cells maintain quiescence is still poorly understood. Here we show that stem cells in the dentate gyrus of the adult hippocampus actively transcribe the pro-activation factor Ascl1 regardless of their activation state. We found that the inhibitor of DNA binding protein Id4 suppresses Ascl1 activity in neural stem cell cultures. Id4 sequesters Ascl1 heterodimerisation partner E47, promoting Ascl1 protein degradation and neural stem cell quiescence. Accordingly, elimination of Id4 from stem cells in the adult hippocampus results in abnormal accumulation of Ascl1 protein and premature stem cell activation. We also found that multiple signalling pathways converge on the regulation of Id4 to reduce the activity of hippocampal stem cells. Id4 therefore maintains quiescence of adult neural stem cells, in sharp contrast with its role of promoting the proliferation of embryonic neural progenitors.

Notch2 signaling regulates Id4 and cell cycle genes to maintain neural stem cell quiescence in the adult hippocampus

“…Ascl1 induces differentiation in the embryonic nervous system and cell cycle entry of quiescent adult NSCs (Andersen et al, 2014). Moreover, recent data show that as a result of binding and sequestering the E-box protein E47, Id4 enhances the degradation of Ascl1, thereby maintaining DG NSC quiescence (Blomfield et al, 2018). These observations all support our findings that Notch2 conveys quiescence to NSCs through Id4.…”

Id4 promotes the elimination of the pro-activation factor Ascl1 to maintain quiescence of adult hippocampal stem cells

“…In agreement with this, Id1 has recently been shown to have a role in the activation of hematopoietic stem cells upon stress signals (Singh et al, 2018). We have addressed the effect of loss of Id1 from RGLs by examining Smad4cKO mice, where Id1 expression in RGLs is greatly reduced while Id4 expression is unaffected (Blomfield et al, 2018). Loss of Smad4 did not affect RGLs, indicating that Id1 is not required to suppress Ascl1 expression or RGL proliferation.…”

“…Id genes, including Id4 , are well known effectors of BMP signalling in neural cells and other cell types (Ling et al, 2014; Patel et al, 2015; Samanta and Kessler, 2004). Smad4 deletion strongly reduces Id1 but not Id4 levels in RGLs, indicating that Id4 diverges from other Id proteins not only in its activity but also in the regulation of its expression (Blomfield et al, 2018). Id4 has been shown to be directly regulated by Notch signalling in embryonic neural progenitors (Li et al, 2012) and in adult hippocampal stem cells (Zhang et al, 2019) but we found that Id4 expression persists in RGLs lacking the essential Notch signalling effector RBPJk (Blomfield et al, 2018).…”

Bone morphogenetic protein signaling regulates Id1 mediated neural stem cell quiescence in the adult zebrafish brain via a phylogenetically conserved enhancer module

“…It remains to be assessed whether the BMP/Id1 and Notch/Her4.1 pathways are redundant or parallel pathways with distinct functions in stem cell maintenance during constitutive and reactive neurogenesis. In mouse it was recently suggested that both Notch/Hes and Bmp/Id pathways interact to enhance quiescence of neural stem cells 47,48 .…”