Department of Biology, Drexel University, 3141 Chestnut St., Philadelphia, PA, 19104, USA.
Program in Molecular and Cellular Biology and Genetics, Drexel University College of Medicine, Philadelphia, PA, USA.
Sci Rep. 2019 Dec 18;9(1):19368. doi: 10.1038/s41598-019-55900-6.
Chromatin remodeling proteins of the chromodomain DNA-binding protein family, CHD7 and CHD8, mediate early neurodevelopmental events including neural migration and differentiation. As such, mutations in either protein can lead to neurodevelopmental disorders. How chromatin remodeling proteins influence the activity of mature synapses, however, is relatively unexplored. A critical feature of mature neurons is well-regulated endocytosis, which is vital for synaptic function to recycle membrane and synaptic proteins enabling the continued release of synaptic vesicles. Here we show that Kismet, the Drosophila homolog of CHD7 and CHD8, regulates endocytosis. Kismet positively influenced transcript levels and bound to dap160 and endophilin B transcription start sites and promoters in whole nervous systems and influenced the synaptic localization of Dynamin/Shibire. In addition, kismet mutants exhibit reduced VGLUT, a synaptic vesicle marker, at stimulated but not resting synapses and reduced levels of synaptic Rab11. Endocytosis is restored at kismet mutant synapses by pharmacologically inhibiting the function of histone deacetyltransferases (HDACs). These data suggest that HDAC activity may oppose Kismet to promote synaptic vesicle endocytosis. A deeper understanding of how CHD proteins regulate the function of mature neurons will help better understand neurodevelopmental disorders.
染色质重塑蛋白家族的 chromodomain DNA 结合蛋白 CHD7 和 CHD8 介导早期神经发育事件，包括神经迁移和分化。因此，这两种蛋白中的任何一种突变都可能导致神经发育障碍。然而，染色质重塑蛋白如何影响成熟突触的活性还相对未知。成熟神经元的一个关键特征是受调控的内吞作用，这对于突触功能至关重要，可回收膜和突触蛋白，使突触小泡持续释放。在这里，我们发现果蝇 CHD7 和 CHD8 的同源物 Kismet 调节内吞作用。Kismet 正向影响转录水平，并与 dap160 和 endophilin B 的转录起始位点和启动子结合，在整个神经系统中发挥作用，并影响 Dynamin/Shibire 的突触定位。此外，kismet 突变体在刺激但非静止突触处表现出减少的 VGLUT（突触小泡标记物）和降低的突触 Rab11 水平。通过药理学抑制组蛋白去乙酰化酶 (HDACs) 的功能，可在 kismet 突变体突触处恢复内吞作用。这些数据表明，HDAC 活性可能与 Kismet 对抗以促进突触小泡内吞作用。更深入地了解 CHD 蛋白如何调节成熟神经元的功能将有助于更好地理解神经发育障碍。
