Stem Cell Quiescence in the Hippocampal Neurogenic Niche Is Associated With Elevated Transforming Growth Factor-β Signaling in an Animal Model of Huntington Disease

Abstract

Cellular proliferation, differentiation, integration, and survival within the adult neural stem cell niche are altered under pathological conditions, but the molecular cues regulating the biology of this niche are mostly unknown. We examined the hippocampal neural stem cell niche in a transgenic rat model of Huntington disease. In this model, progressive cognitive deficits develop at the age of 9 months, suggesting possible hippocampal dysfunction. We found a disease-associated progressive decline in hippocampal progenitor cell proliferation accompanied by an expansion of the pool of 5-bromo-2-deoxyuridine label-retaining Sox-2-positive quiescent stem cells in the transgenic animals. Increments in quiescent stem cells occurred at the expense of cAMP-responsive element-binding protein-mediated neuronal differentiation and survival. Because elevated levels of transforming growth factor-beta1 (TGF-beta1) impair neural progenitor proliferation, we investigated hippocampal TGF-beta signaling and determined that TGF-beta1 induces the neural progenitors to exit the cell cycle. Although phospho-Smad2, an effector of TGF-beta signaling, is normally absent in subgranular stem cells, it accumulated progressively in Sox2/glial fibrillary acidic protein-expressing cells of the subgranular zone in the transgenic rats. These results indicate that alterations in neurogenesis in transgenic Huntington disease rats occur in successive phases that are associated with increasing TGF-beta signaling. Thus, TGF-beta1 signaling seems to be a crucial modulator of neurogenesis in Huntington disease and may represent a target for future therapy.

Deficits in Adult Neurogenesis, Contextual Fear Conditioning, and Spatial Learning in aGfapMutant Mouse Model of Alexander Disease

“…An increase in the proportion of EdU ϩ /NeuN Ϫ /S100␤ Ϫ cells has been described before with the disruption of neurogenesis (Vallières et al, 2002;Kandasamy et al, 2010), but the fact that these undifferentiated cells outnumber the total number of EdUretaining cells found in wild-type mice by twofold at this time point (4 weeks postlabel) is unusual in that fewer cells were labeled at 24 h compared with wild type. Since we have shown that in Gfap ϩ /R236H mice, Ki67 labels GFAP ϩ /Sox2 ϩ cells that appear to be NSCs, we speculate that EdU ϩ /NeuN Ϫ /S100␤ Ϫ cells in the SGZ may also be GFAP ϩ stem cells.…”

Heterozygous modulation of TGF-β signaling does not influence Müller glia cell reactivity or proliferation following NMDA-induced damage

“…Throughout the body, stem cells reside in niches that are characterized through a specific microenvironment, which keeps the stem cells in their quiescent state (Voog and Jones 2010;Ema and Suda 2012). TGF-β1 was shown to be one of several factors in the brain, which maintain the stem cell niche microenvironment (Wachs et al 2006;Kandasamy et al 2010Kandasamy et al , 2011. TGF-β signaling is mediated through specific binding of TGF-β ligands to the TGF-β receptor type II (TβRII), the essential receptor for TGF-β signaling.…”

Hippocampal Neurogenesis in Neurodegenerative Movement Disorders

“…In addition, 8-and 12-month-old transgenic HD rats were extensively analyzed for the effect of transgene expression in DG neurogenesis. A reduced number of hippocampal progenitor cells was accompanied by an expanded quiescent stem cell pool (characterized by BrdU and Sox2 co-expression) and diminished cAMP-responsive element-binding protein (CREB) signaling (Kandasamy et al 2010 ).…”