title: Neuronal and astroglial TGFβ-Smad3 signaling pathways differentially regulate dendrite growth and synaptogenesis.
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.
authors: Epilepsy and Headache Group, Department of Neurology, The First Hospital of Anhui Medical University, Jixi Road 218, Hefei, 230022, China.
authors: Chuan-Yong
authors: CY
authors: Yu
authors: Wei
authors: W
authors: Gui
authors: Hui-Yan
authors: HY
authors: He
authors: Xiao-Shan
authors: XS
authors: Wang
authors: Jian
authors: J
authors: Zuo
authors: Lin
authors: L
authors: Huang
authors: Nong
authors: N
authors: Zhou
authors: Kai
authors: K
authors: Wang
authors: Yu
authors: Y
authors: Wang
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D002478:Cells, Cultured; D019765:Chondroitin ABC Lyase / Q000494:pharmacology; D011508:Chondroitin Sulfate Proteoglycans / Q000096:biosynthesis / Q000235:genetics; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D058580:Neurocan / Q000096:biosynthesis / Q000235:genetics; D009474:Neurons / Q000378:metabolism* / Q000648:ultrastructure; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5 / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D051900:Smad3 Protein / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013226:Status Epilepticus / Q000378:metabolism; D013569:Synapses / Q000648:ultrastructure*; D016704:Synapsins / Q000032:analysis; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology / Q000502:physiology*
chemical_list: D011508:Chondroitin Sulfate Proteoglycans; D017077:Culture Media, Conditioned; D058580:Neurocan; D034741:RNA, Small Interfering; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016704:Synapsins; D053773:Transforming Growth Factor beta1; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5; D019765:Chondroitin ABC Lyase