Regulation of mTOR signaling in the developing cerebral cortex as a point of convergence for multiple autism risk factors

项目摘要/摘要 通过mTOR的信号是发育中的大脑中蛋白质合成的关键调节器，而且许多 自闭症谱系障碍(ASD)和智力残疾(ID)风险基因已被发现影响 MTOR信号并导致脑区/环路或单个细胞水平的生长和连接改变 类型。双特异性酪氨酸磷酸化调节激酶1a基因突变引起 ASD和ID患者以及小鼠的小头畸形和神经元发育不良 模特们。DYRK1A基因突变导致小头畸形和ASD/ID的机制尚不清楚，但 对于确定靶向治疗的发展至关重要。鉴于观察到多个ASD风险 影响整体脑生长的基因表现出mTOR信号的改变和mTOR信号的减少 发育中的大脑皮层与小头畸形、锥体神经元生长不足和缺陷有关。 在行为和认知方面，我们正在验证DYRK1A突变导致小头畸形症的假设， 神经元生长不足和自闭症相关行为缺陷通过mTOR信号失控。 在前一个资助期收集的初步数据表明，mTOR信号在 Dyrk1a突变小鼠大脑皮层发育及基因上调mTOR信号 抑制Pten或IGF-1药物治疗可挽救小头畸形和神经元病 这种模式下的灌木丛。这项提议的两个目的是：1)描述大脑的影响 与DYRK1a临床相关的神经解剖学和行为表型上的皮质Dyrk1a突变 以及2)检验Dyrk1a和mTOR信号的假设 在共同的调控网络中采取行动，影响与ASD相关的大脑发育和行为表型。 该项目的完成将阐明小头畸形、神经细胞畸形的分子和细胞机制。 DYRK1A和其他ASD/ID风险突变导致的生长不足和ASD相关行为缺陷 影响mTOR通路并将指导DYRK1A治疗方法发展的基因 临床人群。

PROJECT SUMMARY/ABSTRACT Signaling through mTOR is a critical regulator of protein synthesis in the developing brain, and numerous autism spectrum disorder (ASD) and intellectual disability (ID) risk genes have been identified that impinge on mTOR signaling and cause altered growth and connectivity at the level of brain areas/circuits or individual cell types. Mutations in dual-specificity tyrosine phosphorylation-regulated kinase 1a (DYRK1A) cause microcephaly and neuronal undergrowth in a subset of individuals with ASD and ID, as well as in mouse models. The mechanisms by which mutations in DYRK1A lead to microcephaly and ASD/ID are unknown but are critical to identify for the development of targeted treatments. Given the observations that multiple ASD risk genes that impact overall brain growth exhibit altered mTOR signaling and that decreased mTOR signaling in the developing cerebral cortex has been linked with microcephaly, pyramidal neuron undergrowth and deficits in behavior and cognition, we are testing the hypothesis that DYRK1A mutations cause microcephaly, neuronal undergrowth and ASD-relevant behavioral deficits through dysregulated mTOR signaling. Preliminary data collected during the previous funding period indicate that mTOR signaling is downregulated in the developing cerebral cortex of Dyrk1a mutant mice, and that upregulation of mTOR signaling via genetic suppression of Pten or pharmacological treatment with IGF-1 can rescue microcephaly and neuronal undergrowth in this model. The two aims of this proposal are designed to: 1) profile the effects of cerebral cortical Dyrk1a mutations on neuroanatomical and behavioral phenotypes relevant to the DYRK1A clinical population and to dysregulated mTOR signaling, and 2) test the hypothesis that Dyrk1a and mTOR signaling act in a common regulatory network to influence ASD-relevant brain growth and behavioral phenotypes. Completion of this project will elucidate molecular and cellular mechanisms of microcephaly, neuronal undergrowth and ASD-relevant behavioral deficits caused by mutations in DYRK1A and other ASD/ID risk genes that impinge on the mTOR pathway and will guide the development of treatments for the DYRK1A clinical population.