Development of the prethalamus is crucial for thalamocortical projection formation and is regulated by Olig2
Development of the prethalamus is crucial for thalamocortical projection formation and is regulated by Olig2
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DOI：
10.1242/dev.097790
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发表时间：
2014-05-01
期刊：
影响因子：
4.6
通讯作者：
Ikenaka, Kazuhiro
中科院分区：
文献类型：
--
作者：
Ono, Katsuhiko;Clavairoly, Adrien;Ikenaka, Kazuhiro
丘脑皮质轴突(TCA)在其神经回路形成的第一步穿过丘脑前部。尽管前丘脑被认为是丘脑皮质投射形成的中间靶点，但对此靶点的分子机制却知之甚少。在这里，我们展示了丘脑前部在这个神经回路的形成中的功能暗示。我们的研究表明，在前体3的脑室区域(VZ)表达的寡核苷酸转录因子调节丘脑前核的形成，在发育的早期，缺失寡核苷酸会导致前丘脑体积缩小，并伴随着丘脑隆起(TE)的扩张。TCAs的延伸在寡核苷酸的背侧丘脑中是杂乱无章的，在寡核苷酸的前脑中TCAs的起始延伸是迟缓的。基因芯片分析显示，包括EphA3和EPHA5在内的几个轴突导向分子在Olob2-KO基底前脑中表达上调。原位杂交显示野生型丘脑前部排除了EphA3和EPHA5的表达，而Opol2的缺失导致了Ephas阴性区域的缩小和EphHA5阳性TE的扩大。分离培养的丘脑前体细胞表明，底物结合的EphA3抑制了丘脑背侧神经元的轴突延伸。这些结果表明，Orig2参与了丘脑前核的正确形成，导致EphA3表达区域被排除，并对正确的TCA形成至关重要。我们的观察是第一份显示前丘脑如何作用于最初的丘脑皮质投射形成的分子机制的报告。
Thalamocortical axons (TCAs) pass through the prethalamus in the first step of their neural circuit formation. Although it has been supposed that the prethalamus is an intermediate target for thalamocortical projection formation, much less is known about the molecular mechanisms of this targeting. Here, we demonstrated the functional implications of the prethalamus in the formation of this neural circuit. We show that Olig2 transcription factor, which is expressed in the ventricular zone (VZ) of prosomere 3, regulates prethalamus formation, and loss of Olig2 results in reduced prethalamus size in early development, which is accompanied by expansion of the thalamic eminence (TE). Extension of TCAs is disorganized in the Olig2-KO dorsal thalamus, and initial elongation of TCAs is retarded in the Olig2-KO forebrain. Microarray analysis demonstrated upregulation of several axon guidance molecules, including Epha3 and Epha5, in the Olig2-KO basal forebrain. In situ hybridization showed that the prethalamus in the wild type excluded the expression of Epha3 and Epha5, whereas loss of Olig2 resulted in reduction of this Ephas-negative area and the corresponding expansion of the Ephas-positive TE. Dissociated cultures of thalamic progenitor cells demonstrated that substrate-bound EphA3 suppresses neurite extension from dorsal thalamic neurons. These results indicate that Olig2 is involved in correct formation of the prethalamus, which leads to exclusion of the EphA3-expressing region and is crucial for proper TCA formation. Our observation is the first report showing the molecular mechanisms underlying how the prethalamus acts on initial thalamocortical projection formation.