Instituto de Neurociencias de Alicante, Consejo Superior de Investigaciones Científicas and Universidad Miguel Hernández, 03550 Sant Joan d'Alacant, Spain.
J Neurosci. 2012 Mar 28;32(13):4372-85. doi: 10.1523/JNEUROSCI.5851-11.2012.
The assembly of neural circuits is dependent upon the generation of specific neuronal subtypes, each subtype displaying unique properties that direct the formation of selective connections with appropriate target cells. Actions of transcription factors in neural progenitors and postmitotic cells are key regulators in this process. LIM-homeodomain transcription factors control crucial aspects of neuronal differentiation, including subtype identity and axon guidance. Nonetheless, their regulation during development is poorly understood and the identity of the downstream molecular effectors of their activity remains largely unknown. Here, we demonstrate that the Lhx2 transcription factor is dynamically regulated in distinct pools of thalamic neurons during the development of thalamocortical connectivity in mice. Indeed, overexpression of Lhx2 provokes defective thalamocortical axon guidance in vivo, while specific conditional deletion of Lhx2 in the thalamus produces topographic defects that alter projections from the medial geniculate nucleus and from the caudal ventrobasal nucleus in particular. Moreover, we demonstrate that Lhx2 influences axon guidance and the topographical sorting of axons by regulating the expression of Robo1 and Robo2 guidance receptors, which are essential for these axons to establish correct connections in the cerebral cortex. Finally, augmenting Robo1 function restores normal axon guidance in Lhx2-overexpressing neurons. By regulating axon guidance receptors, such as Robo1 and Robo2, Lhx2 differentially regulates the axon guidance program of distinct populations of thalamic neurons, thus enabling the establishment of specific neural connections.
神经回路的组装依赖于特定神经元亚型的产生，每种亚型都具有独特的特性，指导与适当靶细胞形成选择性连接。神经祖细胞和有丝分裂后细胞中转录因子的作用是这个过程的关键调节剂。LIM 同源域转录因子控制神经元分化的关键方面，包括亚型身份和轴突导向。尽管如此，它们在发育过程中的调节机制仍知之甚少，其活性的下游分子效应物的身份在很大程度上仍然未知。在这里，我们证明 Lhx2 转录因子在小鼠丘脑皮质连接发育过程中，在不同的丘脑神经元群体中是动态调节的。事实上，Lhx2 的过表达会在体内引起丘脑皮质轴突导向缺陷，而 Lhx2 在丘脑中的特异性条件缺失会产生拓扑缺陷，特别是改变从中脑内侧膝状体和尾侧腹侧基底核的投射。此外，我们证明 Lhx2 通过调节 Robo1 和 Robo2 导向受体的表达来影响轴突导向和轴突的拓扑排序，这些受体对于这些轴突在大脑皮层中建立正确的连接是必不可少的。最后，增强 Robo1 功能可恢复 Lhx2 过表达神经元中的正常轴突导向。通过调节 Robo1 和 Robo2 等轴突导向受体，Lhx2 可以差异化调节不同群体的丘脑神经元的轴突导向程序，从而实现特定的神经连接。
