TGF-β Signaling Specifies Axons during Brain Development
Open accessAbstract
In the mammalian brain, the specification of a single axon and multiple dendrites occurs early in the differentiation of most neuron types. Numerous intracellular signaling events for axon specification have been described in detail. However, the identity of the extracellular factor(s) that initiate neuronal polarity in vivo is unknown. Here, we report that transforming growth factor beta (TGF-beta) initiates signaling pathways both in vivo and in vitro to fate naive neurites into axons. Neocortical neurons lacking the type II TGF-beta receptor (TbetaR2) fail to initiate axons during development. Exogenous TGF-beta is sufficient to direct the rapid growth and differentiation of an axon, and genetic enhancement of receptor activity promotes the formation of multiple axons. Finally, we show that the bulk of these TGF-beta-dependent events are mediated by site-specific phosphorylation of Par6. These results define an extrinsic cue for neuronal polarity in vivo that patterns neural circuits in the developing brain.
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These growth factors may produce non-canonical signaling outside of the Smad transcription factors, such as through the MAPK pathway.
“These growth factors may produce non-canonical signaling outside of the Smad transcription factors, such as through the MAPK pathway40,41.”
From GDF10 is a signal for axonal sprouting and functional recovery after stroke (2015) · cites this paper as [40]
The Results section, “TGF-β Signaling is Mediated by Par6 Phosphorylation” (page unavailable), describes TGF-β receptor signaling through Par6 phosphorylation, supporting a pathway outside Smad-mediated transcription. The paper describes Par6, Smurf1 and RhoA in this pathway, but the passages found do not support MAPK as the example. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn other in vitro systems, TGFβ promotes axonal outgrowth of injured neurons and blockade of TGFβRII alters neuronal polarity and leads to shorter axons.
“In other in vitro systems, TGFβ promotes axonal outgrowth of injured neurons21,22,39,40 and blockade of TGFβRII alters neuronal polarity and leads to shorter axons42.”
From GDF10 is a signal for axonal sprouting and functional recovery after stroke (2015) · cites this paper as [40]
The Results section, “Axon Specification by TGF-β Signaling is Cell Autonomous” (page unavailable), shows that blocking TβR2 signaling in cultured neurons disrupted polarity and reduced the length of their longest neurite. It does not establish that the affected neurons had shorter axons: most lacked a tau-1-positive axon, and the short processes were described as neurites. The injured-neuron clause is attached to other citations, not this one. (LLM, conf=0.86)
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- Authors
- Yi, J. J., Barnes, A. P., Hand, R., Polleux, F., & Ehlers, M. D.
- Affiliations
- Duke Medical Center (US)
- University of North Carolina at Chapel Hill (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Ehlers, Michael D.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2010-07
- Volume
- 142
- Issue
- 1
- Pages
- 144-157
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC2933408
- OpenAlex
- W1991732233
- Cited by
- 284
- References
- 57
- Citations by year
- 2026: 12 · 2025: 5 · 2024: 10 · 2023: 15 · 2022: 18 · 2021: 30 · 2020: 26 · 2019: 15 · 2018: 11 · 2017: 16 · 2016: 13 · 2015: 20 · 2014: 15 · 2013: 24 · 2012: 28
- FWCI
- 9.51
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- Howard Hughes Medical Institute
- National Institute of Mental Health (K01MH080259)
- National Institute of Neurological Disorders and Stroke (R01NS047574)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- TGF-beta signaling, axon specification, neuronal polarity, dendrite formation, TGFBR2, neocortical neurons, axon growth, neural circuit development
- MeSH terms
- Receptor, Transforming Growth Factor-beta Type II, Animals, Axons, Embryo, Mammalian, Neurons, Phosphorylation, Signal Transduction, Transforming Growth Factor beta, Protein Serine-Threonine Kinases, Receptors, Transforming Growth Factor beta, Neocortex, Adaptor Proteins, Signal Transducing, Mice
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