Signaling through BMPR-IA Regulates Quiescence and Long-Term Activity of Neural Stem Cells in the Adult Hippocampus

Abstract

Neural stem cells (NSCs) in the adult hippocampus divide infrequently, and the molecules that modulate their quiescence are largely unknown. Here, we show that bone morphogenetic protein (BMP) signaling is active in hippocampal NSCs, downstream of BMPR-IA. BMPs reversibly diminish proliferation of cultured NSCs while maintaining their undifferentiated state. In vivo, acute blockade of BMP signaling in the hippocampus by intracerebral infusion of Noggin first recruits quiescent NSCs into the cycle and increases neurogenesis; subsequently, it leads to decreased stem cell division and depletion of precursors and newborn neurons. Consistently, selective ablation of Bmpr1a in hippocampal NSCs, or inactivation of BMP canonical signaling in conditional Smad4 knockout mice, transiently enhances proliferation but later leads to a reduced number of precursors, thereby limiting neuronal birth. BMPs are therefore required to balance NSC quiescence/proliferation and to prevent loss of the stem cell activity that supports continuous neurogenesis in the mature hippocampus.

Bone morphogenetic proteins and secreted frizzled related protein 2 maintain the quiescence of adult mammalian retinal stem cells

“…Similar BMP-induced quiescence effects have also been demonstrated in the adult hippocampus to maintain the proliferative potential of subgranular zone neural progenitors [45]. These BMP2 and BMP4 blocking effects on adult RSC proliferation are specific, since the addition of Noggin abolished this inhibition.…”

TGF-β Family Signaling in Neural and Neuronal Differentiation, Development, and Function

“…BMP-2, BMP-4, and BMP-7 are expressed in the SVZ and promote astroglial lineage commitment, whereas noggin suppresses it (Lim et al 2000;Colak et al 2008). In the SGZ, exogenous expression of noggin and BMP-4, or inactivation of either BMPRIA or Smad4 show the role of BMP signaling in the regulation of quiescence and activation of neural stem cells (Bonaguidi et al 2008;Colak et al 2008;Mira et al 2010;Bond et al 2014;Meyers et al 2016). …”

p53 Regulates Neural Stem Cell Proliferation and Differentiation via BMP-Smad1 Signaling and Id1

“…Recent studies show that BMPs help to keep NSC cells at quiescent status in adult mice. Blockade of BMPs action with Noggin-or tissue-specific inactivation of BMPRIA led to eventual decrease of the NSCs in hippocampus compartment [17]. However, little is known about the BMP target genes that control neurogenesis, with the exception of inhibitor of DNA binding 1 (Id1).…”