Canonical TGF-β Signaling Negatively Regulates Neuronal Morphogenesis through TGIF/Smad Complex-Mediated CRMP2 Suppression
Canonical TGF-β Signaling Negatively Regulates Neuronal Morphogenesis through TGIF/Smad Complex-Mediated CRMP2 Suppression
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DOI：
10.1523/jneurosci.2423-17.2018
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发表时间：
2018-05-16
影响因子：
5.3
通讯作者：
Nakashima, Kinichi
中科院分区：
文献类型：
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作者：
Nakashima, Hideyuki;Tsujimura, Keita;Nakashima, Kinichi
功能神经元的连接需要适当的神经元形态发生，其失调会导致神经发育疾病。转化生长因子-β(TGP-β)家族细胞因子在神经元发育中起着关键作用，但对其在神经元形态发育中的作用却知之甚少。在这里，我们表明，在脑发育过程中，Smad依赖的转化生长因子-β家族细胞因子的典型信号负向调节神经元的形态发生。在机制上，激活的Smads与转录抑制因子TG相互作用因子(TGIF)形成一个复合体，并下调神经元极性调节因子-崩塌反应介体蛋白2的表达。我们还证明了转化生长因子-β家族信号通路抑制了人诱导的多能干细胞来源的神经元的轴突延长。此外，在神经发育障碍患者中发现突变的转化生长因子-β受体1、Smad4或TGIF的表达，扰乱了小鼠(男性和女性)和人类(女性)神经元的神经元形态发生。综上所述，这些发现表明，转化生长因子-β信号的进化保守功能对神经元形态发生的调节参与了神经发育疾病的发病机制。
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.