Distinct hyperactive RAS/MAPK alleles converge on common GABAergic interneuron core programs.
Distinct hyperactive RAS/MAPK alleles converge on common GABAergic interneuron core programs.
复制标题
DOI：
10.1242/dev.201371
复制
发表时间：
2023-05-15
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
RAS/MAPK基因功能障碍是各种癌症和神经认知障碍的基础。虽然RAS/MAPK基因在癌症中的作用已经得到了很好的研究，但对其在神经发育过程中的功能知之甚少。有许多基因协同调节RAS/MAPK信号传导，这表明如果能够发现常见的大脑表型，它们可能对由不同的RAS/MAPK基因引起的许多其他疾病产生广泛影响。我们评估了过度激活RAS/MAPK通路的细胞和分子后果，使用两种不同的基因在一种细胞类型中，以前涉及RAS/MAPK介导的认知变化，皮质GABA能中间神经元。我们发现了一些GABA能的核心程序，这些程序在每个突变体中通常都会改变。值得注意的是，过度活跃的RAS/MAPK突变体偏向于生长抑素阳性的皮质中间神经元。生长抑素阳性中间神经元的增加也可以通过药物抑制核心RAS/MAPK信号通路来防止。总的来说，这些发现为不同的RAS/MAPK突变如何聚集在GABA能中间神经元上提供了新的见解，这对其他RAS/MAPK基因和相关疾病可能很重要。总结：通过两种不同的机制在小鼠中过度激活RAS/MAPK通路揭示了不同的RAS/MAPK基因影响GABA能中间神经元的分子和细胞特性，表明可能与RAS/MAPK综合征大家族相关的常见改变。
RAS/MAPK gene dysfunction underlies various cancers and neurocognitive disorders. Although the roles of RAS/MAPK genes have been well studied in cancer, less is known about their function during neurodevelopment. There are many genes that work in concert to regulate RAS/MAPK signaling, suggesting that if common brain phenotypes could be discovered they could have a broad impact on the many other disorders caused by distinct RAS/MAPK genes. We assessed the cellular and molecular consequences of hyperactivating the RAS/MAPK pathway using two distinct genes in a cell type previously implicated in RAS/MAPK-mediated cognitive changes, cortical GABAergic interneurons. We uncovered some GABAergic core programs that are commonly altered in each of the mutants. Notably, hyperactive RAS/MAPK mutants bias developing cortical interneurons towards those that are somatostatin positive. The increase in somatostatin-positive interneurons could also be prevented by pharmacological inhibition of the core RAS/MAPK signaling pathway. Overall, these findings present new insights into how different RAS/MAPK mutations can converge on GABAergic interneurons, which may be important for other RAS/MAPK genes and related disorders. Summary: Hyperactivation of the RAS/MAPK pathway in mouse via two different mechanisms reveals that distinct RAS/MAPK genes influence the molecular and cellular properties of GABAergic interneurons, suggesting common alterations that may be relevant to the large family of RAS/MAPK syndromes.
影响因子：
4.3
作者：
Pai, Emily Ling-Lin;Stafford, April M.;Vogt, Daniel
通讯作者：
Vogt, Daniel