Centro Nacional de Biotecnología (CNB-CSIC), Campus de Cantoblanco, Darwin 3, 28049 Madrid, Spain.
Centro Nacional de Biotecnología (CNB-CSIC), Campus de Cantoblanco, Darwin 3, 28049 Madrid, Spain; Departamento de Matemáticas Universidad Carlos III de Madrid, Grupo Interdisciplinar de Sistemas Complejos (GISC), 28911 Leganés, Madrid, Spain.
Neuron. 2016 Feb 3;89(3):494-506. doi: 10.1016/j.neuron.2015.12.020. Epub 2016 Jan 21.
Neuronal subtype-specific transcription factors (TFs) instruct key features of neuronal function and connectivity. Activity-dependent mechanisms also contribute to wiring and circuit assembly, but whether and how they relate to TF-directed neuronal differentiation is poorly investigated. Here we demonstrate that the TF Cux1 controls the formation of the layer II/III corpus callosum (CC) projections through the developmental transcriptional regulation of Kv1 voltage-dependent potassium channels and the resulting postnatal switch to a Kv1-dependent firing mode. Loss of Cux1 function led to a decrease in the expression of Kv1 transcripts, aberrant firing responses, and selective loss of CC contralateral innervation. Firing and innervation were rescued by re-expression of Kv1 or postnatal reactivation of Cux1. Knocking down Kv1 mimicked Cux1-mediated CC axonal loss. These findings reveal that activity-dependent processes are central bona fide components of neuronal TF-differentiation programs and establish the importance of intrinsic firing modes in circuit assembly within the neocortex.
神经元亚型特异性转录因子 (TFs) 指导神经元功能和连接的关键特征。活动依赖性机制也有助于布线和电路组装,但它们是否以及如何与 TF 指导的神经元分化相关尚未得到充分研究。在这里,我们证明 TF Cux1 通过对 Kv1 电压依赖性钾通道的发育转录调控以及随后的依赖 Kv1 的发射模式的出生后转换来控制 II/III 层胼胝体 (CC) 投射的形成。Cux1 功能丧失导致 Kv1 转录本的表达减少、异常发射反应以及 CC 对侧神经支配的选择性丧失。通过重新表达 Kv1 或出生后重新激活 Cux1 可挽救发射和神经支配。敲低 Kv1 可模拟 Cux1 介导的 CC 轴突丢失。这些发现表明,活动依赖性过程是神经元 TF 分化程序的核心真实组成部分,并确立了内在发射模式在新皮层内电路组装中的重要性。