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Research Database PMU-SQQUID

Stem cell quiescence in the hippocampal neurogenic niche is associated with elevated transforming growth factor-beta signaling in an animal model of Huntington disease.
Kandasamy, M; Couillard-Despres, S; Raber, KA; Stephan, M; Lehner, B; Winner, B; Kohl, Z; Rivera, FJ; Nguyen, HP; Riess, O; Bogdahn, U; Winkler, J; von Hörsten, S; Aigner, L;
J Neuropathol Exp Neurol. 2010; 69(7):717-728
Originalarbeiten (Zeitschrift)

PMU-Authors

Aigner Ludwig
Couillard-Després Sébastien
Rivera Gomez-Barris Francisco J.

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 labelYretaining 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-beta 1 (TGF-beta 1) impair neural progenitor proliferation, we investigated hippocampal TGF-beta signaling and determined that TGF-beta 1 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-beta 1 signaling seems to be a crucial modulator of neurogenesis in Huntington disease and may represent a target for future therapy.


Useful keywords (using NLM MeSH Indexing)

Age Factors

Animals

Animals, Genetically Modified

Bromodeoxyuridine/metabolism

CREB-Binding Protein/metabolism

Cell Proliferation/drug effects

Disease Models, Animal

Gene Expression Regulation/drug effects

Gene Expression Regulation/genetics

Hippocampus/pathology*

Huntington Disease/pathology*

Male

Microtubule-Associated Proteins/metabolism

Models, Biological

Nerve Tissue Proteins/metabolism

Neurogenesis/drug effects

Neurogenesis/genetics*

Neuropeptides/metabolism

Nuclear Proteins

Proliferating Cell Nuclear Antigen/metabolism

Rats

SOXB1 Transcription Factors/metabolism

Signal Transduction/drug effects

Signal Transduction/genetics

Signal Transduction/physiology*

Smad2 Protein/metabolism

Stem Cell Niche/drug effects

Stem Cell Niche/physiopathology*

Transforming Growth Factor beta/metabolism*

Transforming Growth Factor beta/pharmacology

Trinucleotide Repeat Expansion/genetics


Find related publications in this database (Keywords)

Adult neurogenesis
Huntington disease
Neural stem cells
Neuronal differentiation
Proliferation
Transforming growth factor-beta