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Neuronal and Astroglial TGFβ-Smad3 Signaling Pathways Differentially Regulate Dendrite Growth and Synaptogenesis

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Abstract

To address the role of the transforming growth factor beta (TGFβ)-Smad3 signaling pathway in dendrite growth and associated synaptogenesis, we used small inhibitory RNA to knockdown the Smad3 gene in either cultured neurons and or primary astrocytes. We found that TGFβ1 treatment of primary neurons increased dendrite extensions and the number of synapsin-1-positive synapses. When Smad3 was knockdown in primary neurons, dendrite growth was inhibited and the number of synapsin-1-positive synapses reduced even with TGFβ1 treatment. When astrocyte-conditioned medium (ACM), collected from TGFβ1-treated astrocytes (TGFβ1-stimulated ACM), was added to cultured neurons, dendritic growth was inhibited and the number of synapsin-1-positive puncta reduced. When TGFβ1-stimulated ACM was collected from astrocytes with Smad3 knocked down, this conditioned media promoted the growth of dendrites and the number of synapsin-1-positive puncta in cultured neurons. We further found that TGFβ1 signaling through Smad3 increased the expression of chondroitin sulfate proteoglycans, neurocan, and phosphacan in ACM. Application of chondroitinase ABC to the TGFβ1-stimulated ACM reversed its inhibitory effects on the dendrite growth and the number of synapsin-1-positive puncta. On the other hand, we found that TGFβ1 treatment caused a facilitation of Smad3 phosphorylation and translocation to the nucleus induced by status epilepticus (SE) in wild-type (Smad3+/+) mice, and this treatment also caused a promotion of γ-aminobutyric acid-ergic synaptogenesis impaired by SE in Smad3+/+ as well as in Smad3−/− mice, but more dramatic promotion in Smad3+/+ mice. Thus, we provide evidence for the first time that TGFβ-Smad3 signaling pathways within neuron and astrocyte differentially regulate dendrite growth and synaptogenesis, and this pathway may be involved in the pathogenesis of some central nervous system diseases, such as epilepsy.

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Acknowledgments

This work was supported by Natural Science grants to Y Wang (Grant Numbers: 30970997, and 81271444) from the National Natural Science Foundation of China, by Natural Science grants to Y Wang (Grant Number: 09020103008) from Natural Science Foundation of Anhui Province, by Key Scientific and Technological Project to Y Wang (Grant Number: 11010402168) from Anhui Science and Technology Department, and by Natural science grant to N Zhou (Grant Number: KJ2012A175) from the Educational Department of Anhui Province. The authors thank the innominate refers for their reviewing and suggestions.

Conflict of interest

This paper consists of original, unpublished work which is not submitted elsewhere. The authors declare no conflict of interest.

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The protocol for this research project has been approved by the Ethics Committee of the Anhui Medical University within which the work was undertaken and that it conforms to the provisions of the Declaration of Helsinki.

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Authors and Affiliations

  1. Epilepsy and Headache Group, Department of Neurology, The First Hospital of Anhui Medical University, Jixi Road 218, Hefei, 230022, China

    Chuan-Yong Yu, Wei Gui, Hui-Yan He, Jian Zuo, Lin Huang, Nong Zhou & Yu Wang

  2. Department of Neurology, Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, 210029, China

    Chuan-Yong Yu & Xiao-Shan Wang

  3. Department of Neurology, The People’s Hospital of Bozhou, Xuejiaxiang Road 3, Bozhou, 236814, China

    Wei Gui

  4. Department of Neurology, The Fourth Hospital of Anhui Medical University, Tunxi Road 372, Hefei, 230001, China

    Lin Huang

  5. Neuropsychology Group, Anhui Medical University Institute of Neurology, Jixi Road 218, Hefei, 230022, China

    Kai Wang

  6. Department of Neurology, The First Hospital of Anhui Medical University, Jixi Road 218, Hefei, 230022, China

    Kai Wang

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  1. Chuan-Yong Yu
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  9. Yu Wang
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Chuan-Yong Yu, Wei Gui, Hui-Yan He, and Xiao-Shan Wang have contributed equally.

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Yu, CY., Gui, W., He, HY. et al. Neuronal and Astroglial TGFβ-Smad3 Signaling Pathways Differentially Regulate Dendrite Growth and Synaptogenesis. Neuromol Med 16, 457–472 (2014). https://doi.org/10.1007/s12017-014-8293-y

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