Stem cell quiescence in the hippocampal neurogenic niche is associated with elevated transforming growth factor-beta signaling in an animal model of Huntington disease.
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.
Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria.
Mahesh
M
Kandasamy
Sebastien
S
Couillard-Despres
Kerstin A
KA
Raber
Michael
M
Stephan
Bernadette
B
Lehner
Beate
B
Winner
Zacharias
Z
Kohl
Francisco J
FJ
Rivera
Huu Phuc
HP
Nguyen
Olaf
O
Riess
Ulrich
U
Bogdahn
Jürgen
J
Winkler
Stephan
S
von Hörsten
Ludwig
L
Aigner
D000367:Age Factors; D000818:Animals; D030801:Animals, Genetically Modified; D001973:Bromodeoxyuridine / Q000378:metabolism; D050882:CREB-Binding Protein / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006624:Hippocampus / Q000473:pathology*; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000473:pathology*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects / Q000235:genetics*; D009479:Neuropeptides / Q000378:metabolism; D009687:Nuclear Proteins; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D051899:Smad2 Protein / Q000378:metabolism; D055153:Stem Cell Niche / Q000187:drug effects / Q000503:physiopathology*; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
D000089622:Doublecortin Domain Proteins; C499524:Htt protein, rat; D000071058:Huntingtin Protein; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D009687:Nuclear Proteins; D018809:Proliferating Cell Nuclear Antigen; D055748:SOXB1 Transcription Factors; D051899:Smad2 Protein; C497784:Smad2 protein, rat; D016212:Transforming Growth Factor beta; D050882:CREB-Binding Protein; D001973:Bromodeoxyuridine