Dominick P. Purpura Department of Neuroscience Albert Einstein College of Medicine, Bronx, United States.
Department of Genetics Albert Einstein College of Medicine, Bronx, United States.
Elife. 2021 Mar 17;10:e63886. doi: 10.7554/eLife.63886.
Mutations in the lysine demethylase 5 (KDM5) family of transcriptional regulators are associated with intellectual disability, yet little is known regarding their spatiotemporal requirements or neurodevelopmental contributions. Utilizing the mushroom body (MB), a major learning and memory center within the brain, we demonstrate that KDM5 is required within ganglion mother cells and immature neurons for proper axogenesis. Moreover, the mechanism by which KDM5 functions in this context is independent of its canonical histone demethylase activity. Using in vivo transcriptional and binding analyses, we identify a network of genes directly regulated by KDM5 that are critical modulators of neurodevelopment. We find that KDM5 directly regulates the expression of , a transcription factor that we demonstrate is essential for MB morphogenesis. Prospero functions downstream of KDM5 and binds to approximately half of KDM5-regulated genes. Together, our data provide evidence for a KDM5-Prospero transcriptional axis that is essential for proper MB development.
赖氨酸去甲基酶 5 (KDM5) 家族转录调节剂的突变与智力障碍有关，但对于其时空需求或神经发育贡献知之甚少。我们利用蘑菇体（MB），大脑中的主要学习和记忆中心，证明 KDM5 在神经母细胞和未成熟神经元中对于正确的轴突发生是必需的。此外，KDM5 在这种情况下发挥作用的机制与其经典的组蛋白去甲基酶活性无关。通过体内转录和结合分析，我们确定了一个由 KDM5 直接调控的基因网络，这些基因是神经发育的关键调节剂。我们发现 KDM5 直接调控 的表达，我们证明该转录因子对于 MB 形态发生是必需的。Prospero 是 KDM5 的下游靶标，大约结合了 KDM5 调控的一半基因。总之，我们的数据为 KDM5-Prospero 转录轴提供了证据，该轴对于正确的 MB 发育是必不可少的。
