Aging brain microenvironment decreases hippocampal neurogenesis through Wnt-mediated survivin signaling
Carlos J. Miranda
Center for Gene Therapy, Nationwide Children’s Hospital Research Institute, Columbus, OH 43205, USA
Search for more papers by this authorLyndsey Braun
Center for Gene Therapy, Nationwide Children’s Hospital Research Institute, Columbus, OH 43205, USA
Search for more papers by this authorYuying Jiang
Center for Gene Therapy, Nationwide Children’s Hospital Research Institute, Columbus, OH 43205, USA
Search for more papers by this authorMark E. Hester
Center for Gene Therapy, Nationwide Children’s Hospital Research Institute, Columbus, OH 43205, USA
Search for more papers by this authorLing Zhang
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Search for more papers by this authorMatthew Riolo
Division of Hematology-Oncology, Department of Pediatrics, Brown University, Providence, RI 02903, USA
Search for more papers by this authorHaijuan Wang
Division of Hematology-Oncology, Department of Pediatrics, Brown University, Providence, RI 02903, USA
Search for more papers by this authorMeghan Rao
Center for Gene Therapy, Nationwide Children’s Hospital Research Institute, Columbus, OH 43205, USA
Search for more papers by this authorRachel A. Altura
Division of Hematology-Oncology, Department of Pediatrics, Brown University, Providence, RI 02903, USA
Search for more papers by this authorBrian K. Kaspar
Center for Gene Therapy, Nationwide Children’s Hospital Research Institute, Columbus, OH 43205, USA
Department of Neuroscience, College of Medicine, Center for Brain and Spinal Cord Repair, The Ohio State University, Columbus, OH 43210, USA
Search for more papers by this authorCarlos J. Miranda
Center for Gene Therapy, Nationwide Children’s Hospital Research Institute, Columbus, OH 43205, USA
Search for more papers by this authorLyndsey Braun
Center for Gene Therapy, Nationwide Children’s Hospital Research Institute, Columbus, OH 43205, USA
Search for more papers by this authorYuying Jiang
Center for Gene Therapy, Nationwide Children’s Hospital Research Institute, Columbus, OH 43205, USA
Search for more papers by this authorMark E. Hester
Center for Gene Therapy, Nationwide Children’s Hospital Research Institute, Columbus, OH 43205, USA
Search for more papers by this authorLing Zhang
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Search for more papers by this authorMatthew Riolo
Division of Hematology-Oncology, Department of Pediatrics, Brown University, Providence, RI 02903, USA
Search for more papers by this authorHaijuan Wang
Division of Hematology-Oncology, Department of Pediatrics, Brown University, Providence, RI 02903, USA
Search for more papers by this authorMeghan Rao
Center for Gene Therapy, Nationwide Children’s Hospital Research Institute, Columbus, OH 43205, USA
Search for more papers by this authorRachel A. Altura
Division of Hematology-Oncology, Department of Pediatrics, Brown University, Providence, RI 02903, USA
Search for more papers by this authorBrian K. Kaspar
Center for Gene Therapy, Nationwide Children’s Hospital Research Institute, Columbus, OH 43205, USA
Department of Neuroscience, College of Medicine, Center for Brain and Spinal Cord Repair, The Ohio State University, Columbus, OH 43210, USA
Search for more papers by this authorSummary
Accumulating evidence suggests that adult hippocampal neurogenesis relies on the controlled and continued proliferation of neural progenitor cells (NPCs). With age, neurogenesis decreases through mechanisms that remain unclear but are believed to involve changes in the NPC microenvironment. Here, we provide evidence that NPC proliferation in the adult brain is in part regulated by astrocytes via Wnt signaling and that this cellular cross-talk is modified in the aging brain, leading to decreased proliferation of NPCs. Furthermore, we show that astrocytes regulate the NPC cell cycle by acting on the expression levels of survivin, a known mitotic regulator. Among cell cycle genes found down-regulated in aged NPCs, survivin was the only one that restored NPC proliferation in the aged brain. Our results provide a mechanism for the gradual loss of neurogenesis in the brain associated with aging and suggest that targeted modulation of survivin expression directly or through Wnt signaling could be used to stimulate adult neurogenesis.
Supporting Information
Fig. S1 NPCs isolated from 13-month DG morphologically resemble 3-month NPCs and do not show increased levels of cell death or cell heterogeneity.
Fig. S2 Late passage 13-month NPC have a normal karyotype.
Fig. S3 Survivin levels directly correlate with NPC proliferation.
Fig. S4 Survivin levels are higher in NPCs compared with their differentiated progeny.
Fig. S5 Potent anti-apoptotic genes do not compensate for survivin deficiency in NPCs.
Fig. S6 Survivin expression is not required for maintenance of neurons and astrocytes.
Fig. S7 Astrocte-conditioned medium from 13-month astrocytes inhibits Wnt signaling in NPCs.
Table S1 Comparative quantitative RT-PCR analysis of cell cycle gene levels between 3- and 13-month NPCs.
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