School of Life Sciences, Arizona State University, Tempe, AZ 85287, USA.
Department of Pediatrics and Human Development, Michigan State University, Grand Rapids, MI 49503, USA.
Development. 2023 May 15;150(10). doi: 10.1242/dev.201371. Epub 2023 May 31.
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.
RAS/MAPK 基因功能障碍是多种癌症和神经认知障碍的基础。尽管 RAS/MAPK 基因在癌症中的作用已经得到了很好的研究，但它们在神经发育过程中的功能却知之甚少。有许多基因协同作用来调节 RAS/MAPK 信号转导，这表明如果能发现常见的大脑表型，它们可能会对许多由不同 RAS/MAPK 基因引起的其他疾病产生广泛影响。我们使用两种先前被认为与 RAS/MAPK 介导的认知变化有关的细胞类型中的特定基因，评估了 RAS/MAPK 通路的过度激活对细胞和分子的影响。我们发现了一些在每个突变体中都普遍改变的 GABA 能核心程序。值得注意的是，过度活跃的 RAS/MAPK 突变体使发育中的皮质 GABA 能中间神经元向生长抑素阳性的神经元倾斜。通过对核心 RAS/MAPK 信号通路的药理学抑制也可以预防生长抑素阳性中间神经元的增加。总的来说，这些发现为不同的 RAS/MAPK 突变如何能集中在 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。
