Noggin Expands Neural Stem Cells in the Adult Hippocampus

Abstract

New neurons are added to the adult hippocampus throughout life and contribute to cognitive functions including learning and memory. It remains unclear whether ongoing neurogenesis arises from self-renewing neural stem cells (NSC) or from multipotential progenitor cells that cannot self-renew in the hippocampus. This is largely based on observations that neural precursors derived from the subventricular zone (SVZ) can be passaged long-term whereas hippocampal subgranular zone (SGZ) precursors are rapidly depleted by passaging. We demonstrate here that high levels of BMP signaling occur in hippocampal but not SVZ precursors in vitro, and blocking BMP signaling with Noggin is sufficient to foster hippocampal cell self-renewal, proliferation, and multipotentiality using single cell clonal analysis. Moreover, NSC maintenance requires continual Noggin exposure, which implicates BMPs as crucial requlators of NSC aging. In vivo, Noggin is expressed in the adult dentate gyrus and limits BMP signaling in proliferative cells of the SGZ. Transgenic Noggin overexpression in the SGZ increases multiple precursor cell populations, but proportionally increases the glial fibrillary acidic protein (GFAP)+ cell population at the expense of other precursors, suggesting that Noggin acts on NSCs in vivo. To confirm this, we used a dual thymidine analog paradigm to repeatedly label slowly dividing cells over a long duration. We find that small populations of label-retaining cells exist in the SGZ and that Noggin overexpression increases their numbers. Thus, we propose that the adult hippocampus contains a population of NSCs, which can be expanded both in vitro and in vivo by blocking BMP signaling.

A small molecule accelerates neuronal differentiation in the adult rat

“…To further analyze the effect of KHS101 on lineage-specific differentiation, we exposed rat NPCs to the astrocyte-inducing cytokine bone morphogenetic protein 4 (BMP4), which is expressed in the adult neurogenic niches and has been reported to inhibit hippocampal neurogenesis (13)(14)(15)(16). As expected, BMP4 (50 ng/mL) treatment for 4 d increased differentiation to astrocytes (from 0.5 to 10%) within NPC cultures as assessed by immunostaining for the astrocyte marker glial fibrillary acidic protein (GFAP).…”

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). …”

Epigenomic enhancer annotation reveals a key role for NFIX in neural stem cell quiescence

“…Adult stem cells inhabit specialized niches that produce signals controlling their lifelong self-renewal and production of differentiated progeny (Fuchs et al 2004;Riquelme et al 2008;Fuentealba et al 2012;Faigle and Song 2013). In particular, Notch and BMP signaling, activated by ligands presented by differentiating neural precursors in the neurogenic niches, provide negative feedback signals that maintain the quiescent state of SEZ and hippocampal stem cells (Bonaguidi et al 2008;Ables et al 2010;Ehm et al 2010;Imayoshi et al 2010;Mira et al 2010).…”