Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, 57104, USA.
Basic Biomedical Sciences, University of South Dakota Sanford School of Medicine, Vermillion, SD, 57069, USA.
Sci Rep. 2018 Sep 5;8(1):13278. doi: 10.1038/s41598-018-31578-0.
Through the process of neuronal differentiation, newly born neurons change from simple, spherical cells to complex, sprawling cells with many highly branched processes. One of the first stages in this process is neurite initiation, wherein cytoskeletal modifications facilitate membrane protrusion and extension from the cell body. Hundreds of actin modulators and microtubule-binding proteins are known to be involved in this process, but relatively little is known about how upstream regulators bring these complex networks together at discrete locations to produce neurites. Here, we show that Myristoylated alanine-rich C kinase substrate (MARCKS) participates in this process. Marcks cortical neurons extend fewer neurites and have less complex neurite arborization patterns. We use an in vitro proteomics screen to identify MARCKS interactors in developing neurites and characterize an interaction between MARCKS and a CDC42-centered network. While the presence of MARCKS does not affect whole brain levels of activated or total CDC42, we propose that MARCKS is uniquely positioned to regulate CDC42 localization and interactions within specialized cellular compartments, such as nascent neurites.
通过神经元分化过程，新生成的神经元从简单的球形细胞转变为具有许多高度分支过程的复杂扩张细胞。这个过程的早期阶段之一是轴突起始，其中细胞骨架的修饰促进了细胞膜的突起和从细胞体的延伸。已知有数百种肌动蛋白调节剂和微管结合蛋白参与这个过程，但对于上游调节剂如何将这些复杂的网络聚集在离散的位置以产生轴突知之甚少。在这里，我们表明肌球蛋白相关的富含丙氨酸的 C 激酶底物 (MARCKS) 参与了这个过程。Marcks 皮质神经元延伸的轴突较少，且轴突分支模式的复杂性较低。我们使用体外蛋白质组学筛选来鉴定发育中的轴突中的 MARCKS 相互作用物，并描述 MARCKS 与以 CDC42 为中心的网络之间的相互作用。虽然 MARCKS 的存在并不影响大脑中激活或总 CDC42 的水平，但我们提出 MARCKS 可以独特地调节特殊细胞区室（例如新生轴突）内的 CDC42 定位和相互作用。
