BMP Signaling Regulates the Tempo of Adult Hippocampal Progenitor Maturation at Multiple Stages of the Lineage

Abstract

Novel environmental stimuli, such as running and learning, increase proliferation of adult hippocampal neural stem cells (NSCs) and enlarge the population of new neurons. However, it remains unclear how increased numbers of new neurons can be generated in a time frame far shorter than the time required for proliferating stem cells to generate these neurons. Here, we show that bone morphogenetic protein (BMP) signaling in the subgranular zone regulates the tempo of neural progenitor cell (NPC) maturation by directing their transition between states of quiescence and activation at multiple stages along the lineage. Virally mediated overexpression of BMP4 caused NPC cell cycle exit and slowed the normal maturation of NPCs, resulting in a long-term reduction in neurogenesis. Conversely, overexpression of the BMP inhibitor noggin promoted NPC cell cycle entry and accelerated NPC maturation. Similarly, BMP receptor type 2 (BMPRII) ablation in Ascl1 1 intermediate NPCs accelerated their maturation into neurons. Importantly, ablation of BMPRII in GFAP 1 stem cells accelerated maturation without depleting the NSC pool, indicating that an increased rate of neurogenesis does not necessarily diminish the stem cell population. Thus, inhibition of BMP signaling is a mechanism for rapidly expanding the pool of new neurons in the adult hippocampus by tipping the balance between quiescence/ activation of NPCs and accelerating the rate at which they mature into neurons. STEM CELLS

Increased bone morphogenetic protein signaling contributes to age-related declines in neurogenesis and cognition

“…Generation of BMPRII floxed mutant mice (BMPRII fx/fx ) and breeding to Ascl1-CreER TM ; BMPRII flx ; Rosa zsGreen/+ was described previously (Beppu, et al, 2005,Bond, et al, 2014,Kim, et al, 2011). The transgenic mice were maintained with heterozygous floxed or heterozygous wild-type BMPRII and recombined cells expressed zsGreen (ZG) fluorescent reporter.…”

“…Plasmid design and construction is described previously (Bond, et al, 2014). Briefly, pBOB-IRES2-mCherry (LV-Control), pBOB-secBMP4-IRES2-mCherry (LV-BMP4) and pBOB-secNoggin-IRES2-mCherry (LV-Noggin) were created to manipulate BMP signaling.…”

“…BMP signaling regulates NSC fate in both the developing and adult brain (Bond, et al, 2012). In the hippocampus, BMP signaling is regulated by changes in both BMP ligands and inhibitors (Bond, et al, 2014,Gobeske, et al, 2009,Mira, et al, 2010). BMP4 is the primary BMP family member in the adult hippocampus and noggin is its main inhibitor (Lim, et al, 2000,Mikawa and Sato, 2011,Mikawa, et al, 2006).…”

“…BMP4 is the primary BMP family member in the adult hippocampus and noggin is its main inhibitor (Lim, et al, 2000,Mikawa and Sato, 2011,Mikawa, et al, 2006). BMP signaling promotes quiescence of hippocampal NSC/NPC, and inhibition of BMP signaling recruits both NSC and NPC back into cell cycle with accelerated generation of new neurons (Bond, et al, 2014). The pro-neurogenic effect of running correlates with increased expression of noggin, decreased expression of BMP4, and an overall decrease of BMP signaling in the DG (Gobeske, et al, 2009).…”

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). …”