LHX6, MTG8 and MTG16: functions and interactions in cortical interneuron development

抑制性中间神经元在哺乳动物的高级信息处理所在地皮质中起着关键作用。皮质中间神经元的缺陷会导致神经网络失衡，并可能导致自闭症和精神分裂症等神经发育性认知和精神障碍。影响中间神经元成熟并导致认知功能障碍的基因突变已经被确定，但我们还远未了解皮质中间神经元发育的遗传复杂性以及遗传缺陷如何导致疾病。皮质中的中间神经元具有很大的多样性，并且很大程度上不知道这种多样性是如何在发育中的胚胎中建立的。我们发现了两个新的基因，Mtg 8和Mtg 16，在动物模型中与皮质中间神经元发育的主调节因子Lhx 6在确定中间神经元亚型中起作用。我们的目标是了解这三个基因之间的关系，以及它们对胚胎中中间神经元发育的特定要求。我们还将研究由这些蛋白质的作用触发的更广泛的遗传程序，以进一步了解决定中间神经元细胞身份的遗传组成。最终，这些知识不仅在理解基于中间神经元的发育障碍方面非常宝贵，而且在从干细胞产生中间神经元用于移植修复治疗方面也非常宝贵-这是一种已经在动物模型中实验性地用于癫痫疾病的途径。

Inhibitory interneurons play pivotal roles within the cortex, the seat of higher order information processing in mammals. Defects in cortical interneurons cause neural network imbalance and can lead to seizure-based and neurodevelopmental cognitive and psychiatric impairments such as autism and schizophrenia. Genetic mutations affecting interneuron maturation and leading to cognitive dysfunction have been identified but we are far from understanding the genetic complexity of cortical interneuron development and how genetic defects can lead to disorders.There is a large diversity of interneurons in the cortex and it is largely unknown how this diversity is established in the developing embryo. We discovered two novel genes, Mtg8 and Mtg16, that function in concert with the master regulator of cortical interneuron development Lhx6 in the determination of interneuron subtypes in animal models. We aim to understand the relationship between the three genes and their specific requirements for interneuron development in the embryo. We will also examine wider genetic programs that are triggered by the action of these proteins in order to gain further insight into the genetic makeup that dictates interneuron cell identity. Ultimately, this knowledge will be invaluable not only in understanding interneuron-based developmental disorders, but also in the generation of interneurons from stem cells for use in transplantation repair therapies -a route already adopted experimentally for epileptic conditions in animal models.