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

LHX6、MTG8 和 MTG16：皮质中间神经元发育中的功能和相互作用

• 批准号: BB/N009061/1
• 负责人: Nicoletta Kessaris
• 金额: $ 55.73万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FN009061%2F1
• 关键词: LHX6; MTG8; MTG16; functions; interactions

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.

抑制性中间神经元在哺乳动物的高阶信息处理皮层中起着关键作用。皮质中间神经元的缺陷会导致神经网络失衡，并可能导致基于癫痫发作和神经发育的认知和精神障碍，如自闭症和精神分裂症。影响中间神经元成熟并导致认知功能障碍的基因突变已被确定，但我们对皮层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的理解还远远不够。皮层中的中间神经元有很大的多样性，这种多样性是如何在发育中的胚胎中建立起来的，这在很大程度上是未知的。我们发现了两个新基因，Mtg8和Mtg16，它们与皮质中间神经元发育的主要调节因子Lhx6一起决定动物模型中的中间神经元亚型。我们的目的是了解这三个基因之间的关系及其在胚胎中中间神经元发育的特定需求。我们还将研究由这些蛋白质的作用引发的更广泛的遗传程序，以便进一步了解决定中间神经元细胞身份的基因组成。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，而且在从干细胞中产生用于移植修复治疗的中间神经元方面将是无价的——这一途径已经在动物模型中用于实验性癫痫疾病。

项目成果

MTG8 interacts with LHX6 to specify cortical interneuron subtype identity.

• DOI: 10.1038/s41467-022-32898-6
• 发表时间: 2022-09-05
• 期刊: Nature communications
• 影响因子: 16.6

Classes and continua of hippocampal CA1 inhibitory neurons revealed by single-cell transcriptomics.

• DOI: 10.1371/journal.pbio.2006387
• 发表时间: 2018-06
• 期刊: PLoS biology
• 影响因子: 9.8
• 作者: Harris KD;Hochgerner H;Skene NG;Magno L;Katona L;Bengtsson Gonzales C;Somogyi P;Kessaris N;Linnarsson S;Hjerling-Leffler J
• 通讯作者: Hjerling-Leffler J

Transient developmental imbalance of cortical interneuron subtypes presages long-term changes in behavior.

• DOI: 10.1016/j.celrep.2021.109249
• 发表时间: 2021-06-15
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Magno L;Asgarian Z;Pendolino V;Velona T;Mackintosh A;Lee F;Stryjewska A;Zimmer C;Guillemot F;Farrant M;Clark B;Kessaris N
• 通讯作者: Kessaris N

NKX2-1 Is Required in the Embryonic Septum for Cholinergic System Development, Learning, and Memory.

在胚胎隔膜中需要NKX2-1才能进行胆碱能系统的开发，学习和记忆。

• DOI: 10.1016/j.celrep.2017.07.053
• 发表时间: 2017-08-15
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Magno L;Barry C;Schmidt-Hieber C;Theodotou P;Häusser M;Kessaris N
• 通讯作者: Kessaris N

Fine-Tuning Circadian Rhythms: The Importance of Bmal1 Expression in the Ventral Forebrain.

• DOI: 10.3389/fnins.2017.00055
• 发表时间: 2017
• 期刊: Frontiers in neuroscience
• 影响因子: 4.3
• 作者: Mieda M;Hasegawa E;Kessaris N;Sakurai T
• 通讯作者: Sakurai T