Transgenic ablation of doublecortin-expressing cells suppresses adult neurogenesis and worsens stroke outcome in mice
Open accessAbstract
Injury stimulates neurogenesis in the adult brain, but the role of injury-induced neurogenesis in brain repair and recovery is uncertain. One strategy for investigating this issue is to ablate neuronal precursors and thereby prevent neurogenesis, but this is difficult to achieve in a specific fashion. We produced transgenic mice that express herpes simplex virus thymidine kinase (TK) under control of the promoter for doublecortin (Dcx), a microtubule-associated protein expressed in newborn and migrating neurons. Treatment for 14 days with the antiviral drug ganciclovir (GCV) depleted Dcx-expressing and BrdU-labeled cells from the rostral subventricular zone and dentate gyrus, and abolished neurogenesis and associated neuromigration induced by focal cerebral ischemia. GCV treatment of Dcx-TK transgenic, but not WT, mice also increased infarct size and exacerbated postischemic sensorimotor behavioral deficits measured by rotarod, limb placing, and elevated body swing tests. These findings provide evidence that injury-induced neurogenesis contributes to stroke outcome and might therefore be a target for stroke therapy.
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Studies of neural precursor cell ablation focused on structural tissue preservation in the first 24 h after stroke.
“Unfortunately, the studies of neural precursor cell ablation focused on structural tissue preservation in the first 24 h after stroke.43”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [43]
Evidence that neurogenesis contributes to functional neurological recovery comes from studies with transgenic ablation of doublecortin-expressing neural precursor cells and from exogenous delivery of adult neural precursor cells, which reported impaired or enhanced recovery, respectively.
“Meanwhile, evidence that neuro genesis contributes to functional neurological recovery has been obtained in studies with transgenic ablation of neural precursor cells expressing the marker doublecortin43 and in studies with exogenous delivery of adult neural precursor cells,14,15,44 which reported impaired or enhanced neurological recovery, respectively.”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [43]
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- Authors
- Jin, K., Wang, X., Xie, L., Mao, X. O., & Greenberg, D. A.
- Affiliations
- Buck Institute for Research on Aging (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-04-12
- Volume
- 107
- Issue
- 17
- Pages
- 7993-7998
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2867852
- OpenAlex
- W2001915682
- Cited by
- 225
- References
- 51
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 11 · 2023: 9 · 2022: 12 · 2021: 10 · 2020: 14 · 2019: 9 · 2018: 12 · 2017: 15 · 2016: 17 · 2015: 18 · 2014: 20 · 2013: 20 · 2012: 18
- FWCI
- 6.99
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (R01AG021980, AG21980)
- National Institute of Neurological Disorders and Stroke (NS57186, R01NS044921, RL1NS062414, NS62414, R01NS057186, NS 44921)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Neonatal and fetal brain pathology
- Keywords
- adult neurogenesis, stroke, focal cerebral ischemia, doublecortin, ganciclovir, thymidine kinase, subventricular zone, dentate gyrus, infarct size, sensorimotor deficits, stroke treatment
- MeSH terms
- Doublecortin Domain Proteins, Doublecortin Protein, Analysis of Variance, Animals, Brain, Bromodeoxyuridine, Immunohistochemistry, Mice, Transgenic, Microtubule-Associated Proteins, Neurons, Neuropeptides, Thymidine Kinase, Blotting, Western, Ganciclovir, DNA Primers, Simplexvirus, Stroke, Rotarod Performance Test, Mice, Ablation Techniques, Neurogenesis
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