Canonical TGF-β signaling negatively regulates neuronal morphogenesis through TGIF/Smad complex-mediated CRMP2 suppression

Hideyuki Nakashima, Keita Tsujimura, Koichiro Irie, Masataka Ishizu, Miao Pan, Tomonori Kameda, Kinichi Nakashima

Research output: Contribution to journalArticle

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Abstract

Functional neuronal connectivity requires proper neuronal morphogenesis and its dysregulation causes neurodevelopmental diseases. Transforming growth factor-β (TGF-β) family cytokines play pivotal roles in development, but little is known about their contribution to morphological development of neurons. Here we show that the Smad-dependent canonical signaling of TGF-β family cytokines negatively regulates neuronal morphogenesis during brain development. Mechanistically, activated Smads form a complex with transcriptional repressor TG-interacting factor (TGIF), and downregulate the expression of a neuronal polarity regulator, collapsin response mediator protein 2. We also demonstrate that TGF-β family signaling inhibits neurite elongation of human induced pluripotent stem cell-derived neurons. Furthermore, the expression of TGF-β receptor 1, Smad4, or TGIF, which have mutations found in patients with neurodevelopmental disorders, disrupted neuronal morphogenesis in both mouse (male and female) and human (female) neurons. Together, these findings suggest that the regulation of neuronal morphogenesis by an evolutionarily conserved function of TGF-β signaling is involved in the pathogenesis of neurodevelopmental diseases.

Original languageEnglish
Pages (from-to)4791-4810
Number of pages20
JournalJournal of Neuroscience
Volume38
Issue number20
DOIs
Publication statusPublished - May 16 2018

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Transforming Growth Factors
Morphogenesis
Neurons
Cytokines
Induced Pluripotent Stem Cells
Growth Factor Receptors
Neurites
Down-Regulation
Mutation
Brain

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

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Canonical TGF-β signaling negatively regulates neuronal morphogenesis through TGIF/Smad complex-mediated CRMP2 suppression. / Nakashima, Hideyuki; Tsujimura, Keita; Irie, Koichiro; Ishizu, Masataka; Pan, Miao; Kameda, Tomonori; Nakashima, Kinichi.

In: Journal of Neuroscience, Vol. 38, No. 20, 16.05.2018, p. 4791-4810.

Research output: Contribution to journalArticle

Nakashima, Hideyuki ; Tsujimura, Keita ; Irie, Koichiro ; Ishizu, Masataka ; Pan, Miao ; Kameda, Tomonori ; Nakashima, Kinichi. / Canonical TGF-β signaling negatively regulates neuronal morphogenesis through TGIF/Smad complex-mediated CRMP2 suppression. In: Journal of Neuroscience. 2018 ; Vol. 38, No. 20. pp. 4791-4810.
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