Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA; Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD 57104, USA; Department of Pediatrics, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD 57105, USA.
Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA.
Neuron. 2023 Mar 15;111(6):839-856.e5. doi: 10.1016/j.neuron.2023.02.023.
mRNA localization and local translation enable exquisite spatial and temporal control of gene expression, particularly in polarized, elongated cells. These features are especially prominent in radial glial cells (RGCs), which are neural and glial precursors of the developing cerebral cortex and scaffolds for migrating neurons. Yet the mechanisms by which subcellular RGC compartments accomplish their diverse functions are poorly understood. Here, we demonstrate that mRNA localization and local translation of the RhoGAP ARHGAP11A in the basal endfeet of RGCs control their morphology and mediate neuronal positioning. Arhgap11a transcript and protein exhibit conserved localization to RGC basal structures in mice and humans, conferred by the 5' UTR. Proper RGC morphology relies upon active Arhgap11a mRNA transport and localization to the basal endfeet, where ARHGAP11A is locally synthesized. This translation is essential for positioning interneurons at the basement membrane. Thus, local translation spatially and acutely activates Rho signaling in RGCs to compartmentalize neural progenitor functions.
mRNA 的定位和局部翻译使基因表达具有精确的时空控制,特别是在极化、伸长的细胞中。这些特征在放射状胶质细胞(RGC)中尤为明显,RGC 是大脑皮层发育过程中的神经和神经胶质前体细胞,也是迁移神经元的支架。然而,亚细胞 RGC 区室如何完成其多种功能的机制还知之甚少。在这里,我们证明了 ARHGAP11A 在 RGC 基底足突中的 mRNA 定位和局部翻译控制其形态并介导神经元定位。Arhgap11a 转录本和蛋白在小鼠和人类中显示出保守的定位到 RGC 基底结构,这是由 5'UTR 赋予的。适当的 RGC 形态依赖于活跃的 Arhgap11a mRNA 运输和定位到基底足突,ARHGAP11A 在那里被局部合成。这种翻译对于将中间神经元定位到基膜是必不可少的。因此,局部翻译在空间和急性激活 RGC 中的 Rho 信号,从而将神经祖细胞的功能分隔开。