TGFβ-Smad2 Signaling Regulates the Cdh1-APC/SnoN Pathway of Axonal Morphogenesis
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Axon growth is critical to the establishment of neuronal connectivity. The E3 ubiquitin ligase Cdh1-anaphase-promoting complex (Cdh1-APC) and its substrate the transcriptional modulator SnoN form a cell-intrinsic pathway that orchestrates axonal morphogenesis in the mammalian brain. How the Cdh1-APC/SnoN pathway is controlled in the nervous system remained unknown. Here, we report that the TGFβ-regulated signaling protein Smad2 plays a key role in regulating the Cdh1-APC/SnoN pathway in neurons. We find that Smad2 is expressed in primary granule neurons of the developing rat cerebellar cortex. The Smad signaling pathway is basally activated in neurons. Endogenous Smad2 is phosphorylated, localized in the nucleus, and forms a physical complex with endogenous SnoN in granule neurons. Inhibition of Smad signaling by several distinct approaches, including genetic knock-down of Smad2, stimulates axonal growth. Biochemical evidence and genetic epistasis analyses reveal that Smad2 acts upstream of SnoN in a shared pathway with Cdh1-APC in the control of axonal growth. Remarkably, Smad2 knock-down also overrides the ability of adult rat myelin to inhibit axonal growth. Collectively, our findings define a novel function for Smad2 in regulation of the Cdh1-APC/SnoN cell-intrinsic pathway of axonal morphogenesis, and suggest that inhibition of Smad signaling may hold therapeutic potential in stimulating axonal growth after injury in the CNS.
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Activation of Smad2 signaling has also been reported to occur with myelin axonal growth inhibition, and direct activation of Smad2 reduces axonal outgrowth in some preparations.
“However, activation of Smad2 signaling has also been reported to occur with myelin axonal growth inhibition, and direct activation of Smad2 reduces axonal outgrowth in some preparations22,24.”
From GDF10 is a signal for axonal sprouting and functional recovery after stroke (2015) · cites this paper as [24]
The Results report basal Smad2 activation in granule neurons and show that Smad2 knockdown increases axonal length, including on myelin. They do not show that myelin activates Smad2 signaling or that directly activating Smad2 reduces axonal outgrowth; those are stronger claims than the experiments establish. No page numbers are available in our copy. (LLM, conf=0.86)
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References 56 · Cited by 86
- Authors
- Stegmüller, J., Huynh, M. A., Yuan, Z., Konishi, Y., & Bonni, A.
- Affiliations
- Harvard University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2008-02-20
- Volume
- 28
- Issue
- 8
- Pages
- 1961-1969
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6671436
- OpenAlex
- W1973237355
- Cited by
- 86
- References
- 56
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 4 · 2023: 1 · 2021: 4 · 2020: 2 · 2019: 2 · 2018: 4 · 2017: 1 · 2016: 2 · 2015: 6 · 2014: 9 · 2013: 11 · 2012: 9
- FWCI
- 4.18
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Christopher and Dana Reeve Foundation
- Charles A. King Trust
- National Institutes of Health
- National Institute on Alcohol Abuse and Alcoholism (F31 AA014698)
- National Institute of General Medical Sciences (GM077226, T32GM007753, R01GM077226)
- National Institute of Neurological Disorders and Stroke (R01NS051255)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- Smad2, TGF-beta signaling, SnoN, axon growth, granule neurons, cerebellar cortex development, E3 ubiquitin ligase
- MeSH terms
- Animals, Axons, Cell Differentiation, Cerebellar Cortex, Morphogenesis, Nerve Tissue Proteins, Transcription Factors, Signal Transduction, Transforming Growth Factor beta, Rats, Long-Evans, Ubiquitin-Protein Ligase Complexes, Rats, Smad2 Protein, Anaphase-Promoting Complex-Cyclosome
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