期刊
JOURNAL OF NEUROSCIENCE
卷 38, 期 20, 页码 4791-4810出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2423-17.2018
关键词
canonical TGF-beta signaling; CRMP2; neurodevelopmental diseases; neuronal morphogenesis; TGIF
资金
- Japan Society for the Promotion of Science (JSPS) KAKENHI [17H01390]
- Intramural Research Grant for Neurological and Psychiatric Disorders of the National Center of Neurology and Psychiatry [27-7]
- JSPS KAKENHI [16K18391, 16J03827]
- Grants-in-Aid for Scientific Research [16K18391, 17H01390, 16J03827] Funding Source: KAKEN
Functional neuronal connectivity requires proper neuronal morphogenesis and its dysregulation causes neurodevelopmental diseases. Transforming growth factor-beta(TGP-beta) 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-beta 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-beta family signaling inhibits neurite elongation of human induced pluripotent stem cell-derived neurons. Furthermore, the expression of TGF-beta 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-beta signaling is involved in the pathogenesis of neurodevelopmental diseases.
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