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An age-related sprouting transcriptome provides molecular control of axonal sprouting after stroke
Open accessAbstract
Stroke is an age-related disease. Recovery after stroke is associated with axonal sprouting in cortex adjacent to the infarct. The molecular program that induces a mature cortical neuron to sprout a new connection after stroke is not known. We selectively isolated neurons that sprout a new connection in cortex after stroke and compared their whole-genome expression profile to that of adjacent, non-sprouting neurons. This 'sprouting transcriptome' identified a neuronal growth program that consists of growth factor, cell adhesion, axonal guidance and cytoskeletal modifying molecules that differed by age and time point. Gain and loss of function in three distinct functional classes showed new roles for these proteins in epigenetic regulation of axonal sprouting, growth factor-dependent survival of neurons and, in the aged mouse, paradoxical upregulation of myelin and ephrin receptors in sprouting neurons. This neuronal growth program may provide new therapeutic targets and suggest mechanisms for age-related differences in functional recovery.
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“In rodent and primate models of stroke, axonal sprouting and the formation of new connections occurs in motor, somatosensory and premotor areas1–4.”
From GDF10 is a signal for axonal sprouting and functional recovery after stroke (2015) · cites this paper as [3]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Within the post-stroke axonal sprouting transcriptome, Growth and Differentiation Factor 10 (GDF10) is one of the most highly upregulated genes during the initiation of axonal sprouting in peri-infarct cortical neurons in the aged brain.”
From GDF10 is a signal for axonal sprouting and functional recovery after stroke (2015) · cites this paper as [3]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Stroke induces axonal sprouting and the formation of new connections in peri-infarct cortex that link premotor, motor, somatosensory and association areas1–4.”
From GDF10 is a signal for axonal sprouting and functional recovery after stroke (2015) · cites this paper as [3]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“GDF10 is induced in sprouting neurons from aged rats during the initiation phase of axonal sprouting, 7 days after stroke3: 1.32× with microarray and 3× with confirmatory qPCR (p<0.0009) at 7d after stroke3.”
From GDF10 is a signal for axonal sprouting and functional recovery after stroke (2015) · cites this paper as [3]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“As previously shown in other gene systems3,4, nucleotide-modified siRNA delivered directly into the infarct core produces protein knockdown over at least 2 weeks after stroke with GDF10 (Supplementary Fig. 3a).”
From GDF10 is a signal for axonal sprouting and functional recovery after stroke (2015) · cites this paper as [3]
Experimental — accuracy not yet measured
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In the citing paper
“To test this hypothesis, GDF10 gain and loss of function was produced directly from the stroke through sustained release via biopolymer hydrogel, which produces release over 2–3 weeks from the stroke site3,4,28 without altering local inflammation, gliosis, neuronal or vascular structure4.”
From GDF10 is a signal for axonal sprouting and functional recovery after stroke (2015) · cites this paper as [3]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Stroke normally produces a limited pattern of axonal sprouting from motor or somatosensory cortex posteriorly to areas adjacent to or caudal to the stroke2–4,28,29.”
From GDF10 is a signal for axonal sprouting and functional recovery after stroke (2015) · cites this paper as [3]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“After stroke, axonal sprouting has been demonstrated in mice, rats and non-human primates1–4,10,38.”
From GDF10 is a signal for axonal sprouting and functional recovery after stroke (2015) · cites this paper as [3]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“This biopolymer hydrogel releases both small and large molecules over a 3 week period from the infarct core3,4,29.”
From GDF10 is a signal for axonal sprouting and functional recovery after stroke (2015) · cites this paper as [3]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“As reported previously3,4,28,29, stroke alone modestly but significantly induces axonal sprouting in the motor cortex adjacent to the stroke site compared to normal motor system connections (Supplementary Fig. 6b).”
From GDF10 is a signal for axonal sprouting and functional recovery after stroke (2015) · cites this paper as [3]
The cited source says what the claim attributes to it.
In the citing paper
“This experimental design has been validated by other groups conducting similar behavioral4 or tissue outcomes experiments3,4,28,29.”
From GDF10 is a signal for axonal sprouting and functional recovery after stroke (2015) · cites this paper as [3]
The cited source says what the claim attributes to it.
In the citing paper
“Animal number in in vivo quantitative cortical mapping studies utilizes spatial correlation statistics, so sample size was estimated from previous publications with similar mechanistic studies3,4,28,29.”
From GDF10 is a signal for axonal sprouting and functional recovery after stroke (2015) · cites this paper as [3]
In the citing paper
“The spatial orientation and distribution of fibres were shown to be controlled by leucine-rich repeat and IgG domain containing protein 1 (Lingo1) and Nogo receptor 1, which directed the newly formed axons to cortical areas that were otherwise not targeted.72”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [72]
In the citing paper
“In the rat somatosensory whisker barrel field, the ATP-dependent DNA-modifying enzyme α-thalassaemia/mental retardation syndrome X-linked (ATRX) protein, which controls neuronal survival and migration during brain development, contributes to the formation of axonal growth cones, which are stabilised by insulin-like growth factor 1.72”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [72]
In the citing paper
“Indeed, the expression of plasticity-related proteins in neurons differs between young and old animals.”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [72]
In the citing paper
“Lingo1 immuno staining, by contrast, was stronger in neurons of old rats (2 years of age) than in young rats (2 months of age).72”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [72]
In the citing paper
“Thus, insulin-like growth factor 1 was localised mainly to astrocytes in the periinfarct cortex of 2-month-old rats, but exhibited predominantly neuronal labelling in 2-year-old rats.72”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [72]
In the citing paper
“Although evidence is limited to a rather small number of studies, the preserved neurological recovery in old animals argues against specific age limits for neurorestorative treatments.”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [72]
In the citing paper
“Although restorative treat ments can promote neurological recovery in old ani mals,17,26,72,76–79 specific findings in ageing animals72,77–79 and in animals with vascular risk factors80,82,86,87 suggest that the efficacy of new therapeutics might be compromised in elderly patients with risk factors.”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [72]
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Citations
Cites
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Ischemic Cell Death in Brain Neurons
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Petreanu, L., Mao, T., Sternson, S. M., & Svoboda, K. (2009) · Nature · doi:10.1038/nature07709 · Cited by 1,047
Fitch, M. T., & Silver, J. (2008) · Experimental Neurology · doi:10.1016/j.expneurol.2007.05.014 · Cited by 1,007
A Neurovascular Niche for Neurogenesis after Stroke
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“Focal cortical strokes on young (2–4 months old) and aged adult (22–24 months old) F344 or C57BL/6 male rats and mice (Charles River Laboratories) were produced as previously describe”
Self-citationCortical rewiring and information storage
Chklovskii, D. B., Mel, B. W., & Svoboda, K. (2004) · Nature · doi:10.1038/nature03012 · Cited by 717
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Carmichael, S. T. (2006) · Annals of Neurology · doi:10.1002/ana.20845 · Cited by 595
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Metadata
- Authors
- Li, S., Overman, J. J., Katsman, D., Kozlov, S. V., Donnelly, C. J., Twiss, J. L., Giger, R. J., Coppola, G., Geschwind, D. H., & Carmichael, S. T.
- Affiliations
- University of California, Los Angeles (US)
- Drexel University (US)
- University of Michigan (US)
- Corresponding author
- Carmichael, S Thomas
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2010-11-07
- Volume
- 13
- Issue
- 12
- Pages
- 1496-1504
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC3059556
- OpenAlex
- W1981596049
- Cited by
- 329
- References
- 50
- Citations by year
- 2026: 7 · 2025: 14 · 2024: 15 · 2023: 28 · 2022: 17 · 2021: 20 · 2020: 16 · 2019: 34 · 2018: 21 · 2017: 27 · 2016: 20 · 2015: 18 · 2014: 20 · 2013: 20 · 2012: 27
- FWCI
- 9.17
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (NS049041, R01NS045729, NS045729, R01NS041596, NS04733, R01NS049041)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- axonal sprouting, stroke, epigenetic regulation, growth factors, cell adhesion, axon guidance, cytoskeletal proteins, Eph receptors, neuronal survival, cortical neurons, functional recovery
- MeSH terms
- Aging, Animals, Axons, Cells, Cultured, Male, Mice, Inbred C57BL, Rats, Inbred F344, Sensory Receptor Cells, Up-Regulation, Recovery of Function, Stroke, Gene Expression Profiling, Mice, Rats
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