title: Age-dependent and differential effects of Smad7ΔEx1 on neural progenitor cell proliferation and on neurogenesis.
abstract: We recently reported that young (3 to 4months old) mice lacking Exon 1 of the Smad7 gene (S7ΔEx1 mice) show enhanced proliferation of neural stem and progenitor cells (NPCs) in the hippocampal dentate gyrus (DG) and in the subventricular zone (SVZ) of the lateral ventricles. It remained unclear, however, whether this phenotype would persist along aging, the latter typically being associated with a profound decrease in neurogenesis. Analysis of NPCs' proliferation based on the cell cycle marker PCNA in 12month-old S7ΔEx1 mice revealed a reversal of the phenotype. Hence, in contrast to their younger counterparts, 12month-old S7ΔEx1 mice had a reduced number of proliferating cells, compared to wildtype (WT) mice. At the same time, the survival of newly generated cells was enhanced in the aged transgenic animals. 12month-old S7ΔEx1 mice further displayed a reduced level of neurogenesis based on the numbers of cells expressing doublecortin (DCX), a marker for newborn neurons. The reduced neurogenesis in aged S7ΔEx1 mice was not due to a stem cell depletion, which might have occurred as a consequence of hyperproliferation in the young mice, since the number of Nestin and Sox2 positive cells was similar in WT and S7ΔEx1 mice. Instead, Nestin positive cells in the DG as well as primary neurosphere cultures derived from 12month-old S7ΔEx1 mice had a reduced capability to proliferate. However, after passaging, when released from their age- and niche-associated proliferative block, neurospheres from aged S7ΔEx1 mice regained the hyperproliferative property. Further, pSmad2 antibody staining intensity was elevated in the DG and SVZ of 12-month old transgenic compared to WT mice, indicating increased intracellular TGF-beta signaling in the aged S7ΔEx1 mice. In summary, this points toward differential effects of S7ΔEx1 on neurogenesis: (i) a hyperproliferation in young animals caused by a cell autonomous mechanism, and (ii) a TGF-beta dependent modulation of neurogenesis in aged S7ΔEx1 animals that abrogates the cell-intrinsic hyperproliferative properties and results in reduced proliferation, increased stem cell quiescence, and enhanced survival of newly generated cells.
authors.affiliation: Institute of Molecular Regenerative Medicine, Paracelsus Medical University, 5020 Salzburg, Austria; Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University, 5020 Salzburg, Austria.
authors.forename: Julia
authors.initials: J
authors.lastname: Marschallinger
authors.affiliation: Department of Neurology, University Hospital Regensburg, Regensburg, Germany; Ludwig Institute for Cancer Research, Uppsala University, Box 595, BMC, 75124 Uppsala, Sweden.
authors.forename: Monika
authors.initials: M
authors.lastname: Krampert
authors.affiliation: Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University, 5020 Salzburg, Austria; Institute of Experimental Neuroregeneration, Paracelsus Medical University, 5020 Salzburg, Austria.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Couillard-Despres
authors.affiliation: Ludwig Institute for Cancer Research, Uppsala University, Box 595, BMC, 75124 Uppsala, Sweden; Karolinska Institute, Department of Clinical Science, Intervention and Technology (CLINTEC), K53, 14186 Stockholm, Sweden.
authors.forename: Rainer
authors.initials: R
authors.lastname: Heuchel
authors.affiliation: Department of Neurology, University Hospital Regensburg, Regensburg, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Bogdahn
authors.affiliation: Institute of Molecular Regenerative Medicine, Paracelsus Medical University, 5020 Salzburg, Austria; Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University, 5020 Salzburg, Austria. Electronic address: ludwig.aigner@pmu.ac.at.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Aigner
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival; D000089662:Doublecortin Protein; D008297:Male; D051379:Mice; D058953:Neural Stem Cells / Q000502:physiology*; D055495:Neurogenesis; D051906:Smad7 Protein / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D016212:Transforming Growth Factor beta
keywords: Aging; Neural stem cell; Neurogenesis; Proliferation; Smad; TGF-beta signaling