The CB1 Cannabinoid Receptor Drives Corticospinal Motor Neuron Differentiation through the Ctip2/Satb2 Transcriptional Regulation Axis
The CB1 Cannabinoid Receptor Drives Corticospinal Motor Neuron Differentiation through the Ctip2/Satb2 Transcriptional Regulation Axis
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DOI：
10.1523/jneurosci.0681-12.2012
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发表时间：
2012-11-21
影响因子：
5.3
通讯作者：
Galve-Roperh, Ismael
中科院分区：
文献类型：
--
作者：
Diaz-Alonso, Javier;Aguado, Tania;Galve-Roperh, Ismael
发育过程中锥体神经元亚群的产生和特化依赖于复杂的转录因子网络。CB 1大麻素受体是内源性大麻素和大麻活性化合物的主要分子靶点。这种受体已被证明影响神经祖细胞增殖和轴突生长，但其参与神经元分化和功能的影响所造成的改变其信号在大脑发育过程中的成年人是未知的。在这里，我们表明，CB 1受体，通过防止Satb 2（特殊AT丰富的结合蛋白2）介导的镇压，增加Ctip 2（COUP-TF相互作用蛋白2）启动子活性，和Ctip 2阳性神经元的产生。在完全CB 1-/-小鼠和海马能神经元特异性Nex-CB 1-/-小鼠中发现的不平衡的神经源性命运决定诱导皮质脊髓运动神经元生成和脑下连接的明显改变，从而导致成年小鼠熟练运动功能受损。同样，Thy 1-YFP-H小鼠中CB 1受体的遗传缺失引起皮质脊髓束发育的改变。总之，这些数据表明，CB 1受体有助于深层皮层神经元的产生，通过耦合内源性大麻素信号从神经源性龛的内在proneurogenic Ctip 2/Satb 2轴，从而影响适当的大脑下投射神经元的规格和皮质脊髓运动功能在成年期。
The generation and specification of pyramidal neuron subpopulations during development relies on a complex network of transcription factors. The CB1 cannabinoid receptor is the major molecular target of endocannabinoids and marijuana active compounds. This receptor has been shown to influence neural progenitor proliferation and axonal growth, but its involvement in neuronal differentiation and the functional impact in the adulthood caused by altering its signaling during brain development are not known. Here we show that the CB1 receptor, by preventing Satb2 (special AT-rich binding protein 2)-mediated repression, increased Ctip2 (COUP-TF interacting protein 2) promoter activity, and Ctip2-positive neuron generation. Unbalanced neurogenic fate determination found in complete CB1-/- mice and in glutamatergic neuron-specific Nex-CB1-/- mice induced overt alterations in corticospinal motor neuron generation and subcerebral connectivity, thereby resulting in an impairment of skilled motor function in adult mice. Likewise, genetic deletion of CB1 receptors in Thy1-YFP-H mice elicited alterations in corticospinal tract development. Altogether, these data demonstrate that the CB1 receptor contributes to the generation of deep-layer cortical neurons by coupling endocannabinoid signals from the neurogenic niche to the intrinsic proneurogenic Ctip2/Satb2 axis, thus influencing appropriate subcerebral projection neuron specification and corticospinal motor function in the adulthood.