The Solomon H. Snyder Department of Neuroscience, Johns Hopkins Kavli Neuroscience Discovery Institute, The Johns Hopkins School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.
Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht University, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands.
Development. 2024 Nov 15;151(22). doi: 10.1242/dev.204293. Epub 2024 Nov 26.
To form functional circuits, neurons must settle in their appropriate cellular locations, and then project and elaborate neurites to contact their target synaptic neuropils. Laminar organization within the vertebrate retinal inner plexiform layer (IPL) facilitates pre- and postsynaptic neurite targeting, yet the precise mechanisms underlying establishment of functional IPL subdomains are not well understood. Here, we explore mechanisms defining the compartmentalization of OFF and ON neurites generally, and OFF and ON direction-selective neurites specifically, within the developing mouse IPL. We show that semaphorin 6A (Sema6A), a repulsive axon guidance cue, is required for delineation of OFF versus ON circuits within the IPL: in the Sema6a null IPL, the boundary between OFF and ON domains is blurred. Furthermore, Sema6A expressed by retinal ganglion cells (RGCs) directs laminar segregation of OFF and ON starburst amacrine cell dendritic scaffolds, which themselves serve as a substrate upon which other retinal neurites elaborate. These results demonstrate that RGCs, the first type of neuron born within the retina, play an active role in functional specialization of the IPL.
为了形成功能性回路，神经元必须在其适当的细胞位置定居，然后投射并精心构建神经突以接触其目标突触神经丛。脊椎动物视网膜内丛状层 (IPL) 的层状组织促进了突触前和突触后神经突的靶向，但功能 IPL 亚区建立的确切机制尚不清楚。在这里，我们探索了在发育中的小鼠 IPL 中普遍定义 OFF 和 ON 神经突以及 OFF 和 ON 方向选择性神经突分区的机制。我们表明，神经突导向分子 6A (Sema6A)，一种排斥性轴突导向线索，是 IPL 内划分 OFF 与 ON 回路所必需的：在 Sema6a 缺失的 IPL 中，OFF 和 ON 区域之间的边界变得模糊。此外，视网膜神经节细胞 (RGC) 表达的 Sema6A 指导 OFF 和 ON 星爆双极细胞树突支架的层状分离，而这些支架本身又作为其他视网膜神经突发育的基质。这些结果表明，RGC 是在视网膜内产生的第一种神经元，在 IPL 的功能特化中发挥积极作用。
