GPR56 S4 variant is required for microglia-mediated synaptic pruning.
GPR56 S4 variant is required for microglia-mediated synaptic pruning.
复制标题
GPR56 S4 变体是小胶质细胞介导的突触修剪所必需的。
作者：
Li,Tao;Luo,Rong;Schmidt,Rachael;D'Alessandro,Nicholas;Kishore,Priya;Zhu,Beika;Yu,Diankun;Piao,Xianhua
ADGRG 1（也称为GPR 56）在大脑发育和布线中起着关键作用，包括皮层分层，中枢神经系统（CNS）髓鞘形成和发育突触细化。然而，对这种不同功能的基本调节机制还没有完全了解。在这里，我们调查的一个特定的选择性剪接异构体，GPR 56剪接变异体4（S4）的功能，以测试的假设，GPR 56的选择性剪接变异体部分支持其不同的功能。我们使用CRISPR/Cas9创建了一个新的转基因小鼠系，Gpr 56 S4，其中GPR 56 S4被删除。详细的表型分析显示，与对照组相比，Gpr 56/Gpr 45小鼠在皮质结构和CNS髓鞘形成方面没有表现出缺陷。令人兴奋的是，它们显著增加了突触密度，减少了小胶质细胞对突触的吞噬，并损害了眼分离。总之，我们的研究结果支持GPR 56 S4变体对于皮质发育和CNS髓鞘形成是必需的，但对于小胶质细胞介导的突触修剪是必需的。
ADGRG1 (also called GPR56) plays critical roles in brain development and wiring, including cortical lamination, central nervous system (CNS) myelination, and developmental synaptic refinement. However, the underlying mechanism(s) in mediating such diverse functions is not fully understood. Here, we investigate the function of one specific alternative splicing isoform, the GPR56 splice variant 4 (S4), to test the hypothesis that alternative splicing variants of GPR56 in part support its different functions. We created a new transgenic mouse line,Gpr56∆S4, using CRISPR/Cas9, in which GPR56 S4 was deleted. Detailed phenotype analyses show thatGpr56∆S4mice manifest no deficits in cortical architecture and CNS myelination compared to controls. Excitingly, they present significantly increased synapse densities, decreased synapse engulfment by microglia, and impaired eye‐segregation. Taken together, our findings support that the GPR56 S4 variant is dispensable for cortical development and CNS myelination but is essential for microglia‐mediated synaptic pruning.